Advanced nanomaterials for malaria theranostics

1 Introduction

Among infectious diseases, malaria is one of the most prevalent and devastating vector-borne diseases on this planet. Malaria very commonly occurs due to the protozoan parasite, which belongs to the genus Plasmodium. Anopheles mosquitoes usually transmit the malaria parasite through bites on humans. According to the 2025 World Health Organization (WHO) statistics, about 282 million malaria cases were reported, and 610,000 deaths were recorded in 80 countries. Among these fatal rates, 95% are from Africa, and 75% are children under 5 years (WHO, 2025). To avoid the issues related to malaria, a lot of significant efforts have been made throughout the world. Especially, strategies like controlling the vectors, high-speed diagnostic testing tools, vaccination, and chemotherapy are effectively implemented. However, the multidrug-resistant nature of Plasmodium falciparum has diminished the complete eradication efforts toward malaria. To overcome this challenge, additional and more innovative alternative approaches that can have high drug efficacy to overcome the existing resistance mechanisms are highly warranted (Guasch-Girbau and Fernàndez-Busquets, 2021; Keleş et al., 2024; Abbasi et al., 2022; Abbasi, 2026b; Abbasi, 2025).

For many decades and centuries, natural product-based drugs played a crucial role in malaria eradication. Cinchona spp. and Artemisia annua are naturally available medicinal plants and are the source of antimalarial chemicals like artemisinin and quinine, and remain the most effective drugs. Due to the high therapeutic efficacy and fast parasite eradication, the artemisinin-based combination therapies have been the first-line treatment for the early stages of malaria. Figure 1A illustrates various stages of malaria, and the therapeutic drugs at various stages have been depicted (Xu et al., 2026). However, in some parts of Africa and Southeast Asian countries, partial resistance toward artemisinin and related drugs was observed, which hampered the efficacy of artemisinin-based combination therapies. To overcome this hurdle, current therapy approaches are looking forward to various other possibilities from herbal medicines, phytochemical therapy, combination approaches, and other novel drug delivery strategies, which can have great potential for the drug-resistant parasites (Pandian et al., 2021; Lokole et al., 2024; Abbasi and Daliri, 2025; Abbasi, 2025a).

Nanomaterials have been attractive and demonstrated their potential in various applications, including health, energy, infectious diseases, and the environment, due to their outstanding features. Such features as a high surface-to-volume ratio, tunable surface chemistry, and functionalization; outstanding physicochemical properties such as mechanical, electrical, and optical; excellent sensing capability; biocompatibility; and economic preparation make them suitable for use in many diagnostic tools and therapeutic drugs directly or as drug carriers (Gollavelli et al., 2022a, Gollavelli et al., 2022b, Gollavelli et al., 2026). The individual and multifunctional nanomaterials have shown potential antimalarial activity in recent studies (Gollavelli et al., 2024). As seen in Figure 1B, a plethora of nanomaterials, such as metals, metal oxides, carbon-based nanomaterials, polymers, lipids, and nanocomposites, have been well reported for antimalarial activity. The graph in Figure 1C shows the overall publication trend in the last five years from 2021 to 2025. Maximum number of articles was published in 2023 and decreased gradually. Despite its decline in growth, it still maintains the level of research, suggesting the continuation of expansion.

Moreover, green-synthesized nanoparticles and surface-functionalized nanomaterials have shown good antiplasmodial activity while decreasing systemic toxicity and enhancing the pharmacokinetic profiles. These nano-based medical procedures have turned up as appealing substitutes to mainstream formulations and may come up with ways to conquer multidrug resistance, enhance patient compliance, and speed up malaria eradication strategies (Sharma et al., 2023; Guasch-Girbau and Fernàndez-Busquets, 2021; Borgheti-Cardoso et al., 2020; Barati et al., 2024; Lokole et al., 2024; Abbasi, 2025b; Abbasi, 2026a). Though many reviews have separately discussed the nanomaterials-based diagnosis and therapy, an integrated critical review emphasizing metal, metal oxides, carbon-based nanomaterials, polymer, and lipid nanomaterials remain lacking in this field to take further in clinical trials. Hence, we reviewed recent advancements in diagnosis, therapy, mechanism of action, cytotoxicity, environmental impacts, translational potential of various advanced nanomaterials, and research gaps along with future perspectives and challenges in this comprehensive review.

2 Metal-based nanomaterials

2.1 Gold nanoparticles

AuNPs have emerged as highly versatile nanomaterials for malaria diagnosis, therapy, and prevention, driven by their distinctive optical, physicochemical, and biological properties. Green-synthesized AuNPs derived from biological sources have gained increasing attention due to their intrinsic anti-plasmodial activity and improved biocompatibility, making them promising candidates for sustainable malaria intervention strategies (Murugan et al., 2015). Beyond therapeutic applications, AuNPs have also been widely explored as powerful diagnostic platforms owing to their localized surface plasmon resonance (LSPR) properties, which enable highly sensitive, rapid, and visually detectable colorimetric and biosensing responses. For instance, Alnasser et al, developed a simple colorimetric assay for the detection of Plasmodium vivax in urine using MSP10-specific oligonucleotides functionalized with AuNPs (Alnasser et al., 2016). The diagnostic platform produced a visible color change upon target recognition, eliminating the need for sophisticated instrumentation and making it suitable for field-based malaria surveillance. The assay demonstrated a sensitivity of 84% and a specificity of 97% for P. vivax detection, with only limited cross-reactivity (21%) toward P. falciparum. Importantly, the use of urine as a non-invasive sample improved patient compliance and reduced the risks associated with blood collection. These findings highlight the potential of AuNP-based colorimetric biosensors as rapid, low-cost, and user-friendly diagnostic tools for malaria detection in resource-limited settings. Table 1 shows various types of AuNPs.

Table 1. Summary of Gold nanoparticle (AuNP) applications in Malaria diagnosis, therapy, and vaccine development.

Subsequent research expanded the role of AuNPs beyond direct antiparasitic activity toward targeted therapeutic delivery. A significant advancement was reported by Varela-Aramburu et al., 2020 who developed ultra-small glucose-coated gold nanoclusters (~2 nm) capable of selectively targeting cysteine-rich proteins expressed by P. falciparum (Figure 2). These nanoclusters interacted effectively with extracellular parasites and all major intraerythrocytic stages, including ring, trophozoite, and schizont forms. Furthermore, conjugation of ciprofloxacin to the gold nanoclusters enhanced drug solubility, cellular uptake, and antiplasmodial efficacy compared with the free drug while exhibiting negligible hemolytic toxicity toward erythrocytes. This work demonstrated the potential of AuNPs as precision drug-delivery vehicles capable of improving therapeutic outcomes while minimizing off-target effects.

In another study, Jayaseelan et al. reported the green synthesis of AuNPs using medicinal plant extracts as an eco-friendly approach for malaria intervention (Jayaseelan et al., 2024). The synthesized AuNPs exhibited significant antiplasmodial activity against Plasmodium falciparum, with inhibitory concentrations varying depending on the plant source. Among the tested formulations, AuNPs derived from Senna auriculata showed the strongest activity, with an IC₅₀ value of approximately 20 μg/mL. The nanoparticles also demonstrated low cytotoxicity toward normal human cells (CC₅₀ > 400 μg/mL), indicating a favorable safety profile and high selectivity index. This study highlights that phytochemical-mediated AuNPs provide a biocompatible, sustainable, and effective nanoplatform for antimalarial applications, combining therapeutic efficacy with reduced host toxicity.

Interestingly, Kumar et al. investigated AuNP-based nanovaccines for malaria using the Plasmodium falciparum transmission-blocking antigen Pfs25 (Kumar et al., 2015). The recombinant Pfs25 antigen was successfully conjugated to AuNPs of varying shapes and sizes, enabling efficient delivery of antigen and enhanced immune presentation. Immunization studies in mice demonstrated that AuNP-conjugated Pfs25 induced strong transmission-blocking antibody responses compared with soluble antigen formulations. The AuNP platform further improved immunogenicity by promoting enhanced uptake by antigen-presenting cells and more efficient antigen processing. Overall, this study highlights AuNPs as effective vaccine carriers that strengthen transmission-blocking immunity and support nanovaccine development for malaria control.

2.2 Silver nanoparticles

AgNPs have emerged as one of the most extensively investigated nanomaterials in malaria control because of their potent, broad-spectrum biocidal activity, comparatively low production cost, and ability to act on both Plasmodium parasite and its Anopheles mosquito vectors simultaneously. At the nanoscale, AgNPs exhibit markedly higher surface-area-to-volume ratio, enhanced chemical reactivity, and a distinctive localized surface plasmon resonance that together account for its expanded pharmacological and diagnostic potential (Sinha et al., 2024).

The antiplasmodial and larvicidal activity of AgNPs involves multiple mechanisms rather than a single pathway. Released Ag⁺ ions bind to the parasite or larval cell membrane, disrupting its integrity and increasing permeability; this allows essential intracellular metabolites to leak out and ultimately drives cell death (Dkhil et al., 2021). Simultaneously, AgNPs exposure raises intracellular reactive oxygen species (ROS) by depleting antioxidant defenses like glutathione, which facilitates apoptosis-like death involving caspase-3 and calpain activation and a shift in the Bax/Bcl-2 expression ratio (Avitabile et al., 2020). Additionally, silver ions bind to thiol and phosphate groups in proteins and nucleic acids, inactivating essential enzymes and fragmenting parasite DNA. Specific proteins from the Plasmodium species, such as M18 aspartyl aminopeptidase and Pf12p, are potential targets of AgNPs derived from different biological sources (Singh et al., 2024). The relative contribution of each mechanism appears to vary with particle size, shape, surface coating, and the biological source used for synthesis.

AgNPs have demonstrated potent antiplasmodial activity both in vitro and in vivo; however, their efficacy depends on the biological source and synthesis method. For instance, Green-synthesized AgNPs derived from Terminalia bellirica leaf extract have demonstrated promising antimalarial potential (shown in Figure 3). In silico molecular docking identified four phytoconstituents from the leaves with strong binding affinities (-9.93 to -11.25 kcal/mol) toward cysteine-rich proteins of Plasmodium species, suggesting their potential as therapeutic candidates and exhibited an IC₅₀ of 94.70 ng/mL against P. falciparum 3D7; whereas Artemisia abrotanum-derived particles demonstrated more efficacy (IC₅₀ of 0.05 µg/mL) by ceasing parasite maturation at the ring stage (Avitabile et al., 2020). Similarly, Euphorbia cotinifolia-derived AgNPs induced apoptosis and DNA fragmentation at 0.75 µg/mL, while myco-synthesized multi-twinned AgNPs completely inhibited P. falciparum at 1 µg/mL. It is also observed that biogenically synthesized AgNPs using plant extracts and microbial extracts exhibit superior efficacy and safety compared to the chemically synthesized AgNPs, attributed to the presence of secondary metabolites in extracts (Singh et al., 2024). For example, AgNPs synthesized from Sargassum tenerrimum, Carica papaya, and Indigofera oblongifolia outperformed their chemically synthesized counterparts in reducing parasitaemia in murine malaria models with minimal toxicity (Veeragoni et al., 2023; Dkhil et al., 2021).

Beyond direct antiparasitic therapy, AgNPs demonstrated larvicidal, ovicidal, and adulticidal activity against Anopheles species. However, the vector-control literature warrants particular caution: several widely cited reports of AgNP larvicidal activity against Anopheles stephensi and related species have been formally retracted, underscoring the need for independent validation before efficacy claims. Due to their localized surface plasmon resonance, AgNPs have also been explored in colorimetric or biosensing detection of Plasmodium biomarkers, although these applications remain less developed than AuNPs (Sinha et al., 2024). Molecular dynamics and density-functional simulations indicate that AgNPs may serve as drug delivery platforms artemisinin-class antimalarials, though this has yet to be validated in biological systems.

Though promising as far as antiplasmodial activity and vector control potential are concerned, there are several challenges that limit the clinical translation of AgNPs. Biogenic AgNPs have relatively better biocompatibility and high efficiency compared to chemically produced AgNPs (Avitabile et al., 2020; Veeragoni et al., 2023); however, their biological activity depends largely on particle size, surface chemistry, and synthesis method, making them non-reproducible from one study to another. Additionally, dose-dependent cytotoxicity, lack of data regarding the environmental safety of AgNPs, and absence of standard regulatory guidelines remain major concerns (Kakakhel et al., 2021; Sinha et al., 2024). So far, most of the evidence available is mainly based on in vitro tests and animal studies without being tested on different Plasmodium species and in a clinical setting (Singh et al., 2024; Sinha et al., 2024; Kakakhel et al., 2021). Therefore, future studies should aim at developing standard methods of green synthesis, nanotoxicity evaluation, large-scale in vivo testing, and functionalization/hybridization of AgNPs to increase efficacy and targeting abilities. Overall summary of Ag nanomaterials in malaria research is shown in Table 2.

Table 2. Comparative analysis of AgNPs applications in malaria research.

2.3 Iron oxide nanoparticles (Fe₃O₄, γ-Fe₂O₃)

Iron oxide nanoparticles (IONPs), mostly magnetite (Fe₃O₄) and maghemite (γ-Fe₂O₃), represent one of the most promising multifunctional nanoplatforms for malaria diagnosis, therapy, and vaccination because of their unique magnetic properties, high biocompatibility, and clinical safety. In comparison with many other metal nanoparticles, some IONPs have been approved by health agencies as MRI contrast agents and iron replacement drugs, offering a notable advantage for their clinical translation into malaria applications (Laurent et al., 2008). IONPs are often made by co-precipitating ferric (Fe³⁺) and ferrous (Fe²⁺) salts. However, methods like hydrothermal, solvothermal, thermal decomposition, microemulsion, and green synthesis offer better control over particle size and surface properties (Laurent et al., 2008). Their superparamagnetic behavior allows for magnetic guidance under an external field without residual magnetization. Surface functionalization with polymers like dextran, polyethylene glycol (PEG), pullulan, and chitosan improves colloidal stability, biocompatibility, circulation time, and the attachment of drugs, antigens, or targeting ligands (Laurent et al., 2008). Notably, biodegradable pullulan-coated IONPs (56–67 nm) have been developed as promising malaria vaccine carriers. Their size helps with efficient uptake by antigen-presenting cells. The functionalized polysaccharide shell allows for stable antigen attachment without hurting biocompatibility (Al-Abboodi et al., 2026). A detailed summary of IONPs for Malaria diagnosis, therapy, and vaccination was shown in Table 3.

Table 3. Comparative analysis of IONPs for malaria diagnosis, therapy, and vaccination.

The primary mechanism underlying IONP utility in malaria management is their superparamagnetism, which enables external magnetic field-directed control over particle movement and accumulation within infection sites. This process helps to concentrate drug-loaded IONPs at the parasite infection site and reduces systemic exposure, magnetically separates malaria-infected erythrocytes from blood, and guides nanovaccine carriers to lymph nodes or antigen-presenting cell depots (Figure 4). Additionally, Plasmodium-infected erythrocytes gain paramagnetic properties during the intraerythrocytic stage because the parasite converts toxic heme, released from hemoglobin digestion, into crystalline hemozoin. This magnetic property allows for the selective enrichment and isolation of infected erythrocytes using high-gradient magnetic separation (HGMS). This method offers a simple and label-free way to detect and enrich parasites. Besides magnetic targeting, functionalized IONPs can improve the effectiveness of antimalarial drugs by releasing Fe²⁺ ions in acidic conditions. These ions catalyze the cleavage of the endoperoxide bridge in artemisinin derivatives, such as artesunate, through Fenton-like reactions. This generates reactive radical species that help kill the parasites. Moreover, biodegradable IONPs act as efficient vaccine carriers by aiding antigen uptake and cross-presentation by dendritic cells. This action stimulates both humoral and cellular immune responses (Powles et al., 2020).

The multifunctional properties of IONPs have led to a broad spectrum of applications in malaria diagnosis, treatment, and vaccination. The most established application is that of isolating Plasmodium-infected erythrocytes via their paramagnetic behavior due to the presence of hemozoin inside these red blood cells. HGMS and magnetophoresis have been extensively used for isolating P. falciparum-infected erythrocytes from the sample, which results in a more accurate detection of parasites, especially at a low parasitemia infection level. Modification of IONPs with anti-parasite surface antigens like PfEMP1 allows for the isolation of infected erythrocytes even at an early infection stage (Kannan et al., 2019).

In addition to parasite enrichment, IONPs have been successfully explored as theranostics platforms through combining diagnosis with drug delivery. As T₂ MRI contrast agents, IONPs allow visualization of brain malaria pathology, while endogenous hemozoin can further contribute to the MRI-based parasite burden detection. Despite the fact that these approaches are mostly preclinical, examples of clinically approved IONPs such as ferumoxytol illustrate the translational value (Pusic et al., 2013). Magnetic targeting can help accumulate IONPs loaded with drugs at infection sites, which increases their efficacy and decreases side effects. Artésunate-loaded Fe₃O₄ nanoparticles demonstrated increased efficiency in killing parasites in the P. berghei-infected mice due to catalytic activation of the drug, while heparin-modified hollow mesoporous ferrite nanoparticles specifically recognized P. falciparum-infected erythrocytes and delivered more artemisinin locally (Kannan et al., 2019). Additionally, Wang et al. developed a multifunctional antimalarial nanoplatform comprising heparin-coated magnetic hollow mesoporous ferrite nanoparticles (HMFN@ART@HEP) for the targeted delivery of artemisinin to Plasmodium falciparum-infected erythrocytes. The magnetic ferrite nanoparticles selectively accumulated around infected red blood cells through interactions with paramagnetic hemozoin, resulting in localized artemisinin delivery and sustained drug release that significantly enhanced parasite inhibition (shown in Figure 5). Simultaneously, the heparin coating effectively blocked merozoite invasion into healthy erythrocytes via multivalent interactions with parasite surface ligands, providing an additional mechanism to suppress parasite propagation. The nanoplatform exhibited excellent biocompatibility, low hemolytic activity, and markedly improved antimalarial efficacy compared with free artemisinin or heparin alone, including a substantial reduction in the IC₅₀ of heparin through nanoparticle-mediated delivery. By integrating magnetic targeting, controlled drug release, and invasion inhibition into a single system, this study highlights the potential of multifunctional magnetic nanocarriers to overcome conventional therapeutic limitations and improve malaria treatment outcomes (Wang et al., 2021).

Apart from diagnosis and therapy, the use of biodegradable IONPs as vehicles for nanovaccines has gained traction recently. The use of dextran-coated IONPs coupled with P. yoelii antigens and, most recently, pullulan-coated IONPs loaded with MSP4/5 showed potent humoral and cellular immune responses to the antigens and better safety profiles than traditional adjuvants. In the same line, SPIONs-based magnetic guidance system increased DNA vaccine delivery efficacy and antibody secretion in vivo (Powles et al., 2020).

Overall, IONPs have advantages over other metallic nanomaterials with respect to biocompatibility, biodegradability, clinical approval history, and magnetic responsiveness, which can be used in a variety of applications, including parasite detection, targeted drug delivery, and vaccine development. But there are still several challenges before they can be broadly translated to the clinic. Efficient magnetic targeting in deep tissues is limited by field penetration and blood flow dynamics. Magnetite oxidation can potentially degrade magnetic performance during prolonged circulation. In addition, the excessive release of iron may induce oxidative stress in host tissues. Most of the existing evidence is limited to in vitro studies or mouse models of malaria. Therefore, future research should aim at the development of multifunctional and stimuli-responsive IONPs with enhanced targeting specificity, standardized physicochemical characterization, and extensive preclinical evaluation in clinically relevant malaria models for their translation into practical diagnostic and therapeutic platforms.

2.4 Zinc oxide nanoparticles

ZnO NPs have attracted substantial interest in malaria control owing to their broad-spectrum antiplasmodial, larvicidal, and antimicrobial activities, photocatalytic properties, excellent biocompatibility, and Generally Recognized as Safe (GRAS) classification by the US Food and Drug Administration. Due to their high surface-area-to-volume ratio, wide bandgap, and enhanced surface reactivity, they can efficiently generate ROS and release Zn²⁺ ions, making them promising multifunctional nanomaterials for integrated malaria control strategies. ZnO NPs can be synthesized chemically, physically, and in environmentally friendly ways; however, the latter, which is environmentally safe and employs the use of natural reducing and stabilizing agents from plants or microorganisms, has been considered a better choice nowadays. Synthesis of ZnO NPs using the extracts of Lagenaria siceraria, Rhazya stricta, Pulicaria undulata, Cuscuta reflexa, and Eucalyptus species has produced stable NPs with potent biological activity against both Plasmodium parasites and Anopheles mosquitoes (Kalpana et al., 2020; Najoom et al., 2021).

The antiplasmodial and larvicidal activities of ZnO NPs are attributable to three partially overlapping mechanisms. The primary mechanism of ZnO NPs toxicity involves the photocatalytic generation of ROS, which triggers oxidative stress resulting in the breakdown of lipids and proteins, damage to DNA, and finally causing cell death in the parasites/mosquitoes (Raghupathi et al., 2011). The second mechanism involves the slow release of Zn²⁺ ions, which interfere with the functioning of critical metabolic enzymes and are said to hinder the formation of hemozoin in P. falciparum, thus causing an increase in free heme in the parasitized cells (Mardani-Talaee et al., 2025). The third mechanism involves direct physical contact between ZnO NPs and biological membranes that causes mechanical disruption of membrane integrity, mainly in mosquito larvae, thereby enhancing the larvicidal and antiparasitic effect of ZnO NPs (Kalpana et al., 2020). A detailed summary of ZnO nanomaterials in malaria research was shown in Table 4.

Table 4. Literature comparison table: ZnO NPs in malaria research.

The above processes have contributed greatly to a diverse application of ZnO NPs in malaria management. Green-synthesized ZnO NPs from Lagenaria siceraria and Rhazya stricta proved to exhibit considerable concentration-dependent antiplasmodial activities against Plasmodium falciparum, outperforming plant extracts in most cases, suggesting that nanoformulation improves the delivery of phytochemicals and zinc ion-induced toxicity (Najoom et al., 2021). Concurrently, many plant-based and microbial ZnO NPs have displayed impressive larvicidal, ovicidal, and adulticidal activities on Anopheles mosquitoes by causing severe pathological damage to the larval midgut and integument via the production of ROS, Zn²⁺ ions, and membrane disruption. Some other researchers have also highlighted the synergism when using ZnO NPs in combination with other larvicides and biological control agents for lowering effective dose and the chances of insecticide resistance (Murugan et al., 2016). Besides its role in parasite killing, ZnO nanoparticles have also been studied as drug delivery systems because of their large surface area and ease of surface modification; however, such systems for delivering drugs specific to malaria are still in their infancy stages. Moreover, the antibacterial properties of these nanoparticles against both Gram-positive and Gram-negative bacteria can serve as another benefit for malaria treatment.

Recently, acorn fruit extract, a phytochemical-rich and sustainable bioresource, was employed for the green synthesis of ZnO NPs, followed by evaluation of their antimicrobial and larvicidal activities (Umar et al., 2026). The successful formation of ZnO NPs was confirmed by the visible transition from yellowish to dark brown color and comprehensive physicochemical characterization, including UV-Vis spectroscopy, FTIR, XRD, and SEM analysis. FTIR analysis revealed characteristic Zn-O stretching vibrations within the 600–450 cm^-¹ region, while XRD patterns confirmed the highly crystalline nature of ZnO, and SEM demonstrated nanoscale morphology with favorable surface characteristics (shown in Figure 6). The biosynthesized ZnO NPs exhibited potent concentration-dependent antibacterial activity against Escherichia coli and Staphylococcus aureus, achieving maximum inhibition zones of 24 ± 5 mm and 26 ± 2 mm, respectively, at 80 µg/mL. Molecular docking studies further revealed strong interactions between ZnO NPs and key residues within the β-lactamase active site, with a binding affinity of 8.2 kcal/mol, suggesting their potential role in suppressing antibiotic resistance mechanisms (Raghupathi et al., 2011). Additionally, ZnO NPs displayed significant larvicidal efficacy against Culex quinquefasciatus larvae, with LC₅₀ and LC₉₀ values of 13.6 and 45 ppm, respectively, inducing severe histopathological alterations, including microvilli degradation, midgut epithelial disruption, cellular vacuolization, and larval mortality (Umar et al., 2026). Overall, this study highlights acorn-mediated ZnO NPs as eco-friendly multifunctional nanomaterials with promising applications in antimicrobial therapeutics, antibiotic resistance management, and mosquito vector control.

Overall, ZnO NPs offer several advantages in the control of malaria infections, including low cost, a simple green synthesis approach, good biocompatibility, and dual targeting effects against both the Plasmodium parasites and Anopheles mosquitoes. The distinctive mechanism of action of the nanoparticles also allows overcoming resistance to conventional antimalarial drugs. However, there are some obstacles to the clinical use of these particles. These include dose-dependent cytotoxicity due to the excessive production of ROS and Zn², environmental toxicity concerning other non-target aquatic species, and low reproducibility of the green synthesis methods (Zolfaghari et al., 2026). What is more, the existing data are mainly based on in vitro experiments and animal models, while full pharmacokinetic studies, biodistribution, long-term toxicity, and clinical trials are still to be done. Research efforts must therefore be geared toward standardization of synthesis methods, physicochemical property optimization, designing of multifunctional and targeted ZnO-based nanomaterials, and thorough pre-clinical testing so that they can be translated to safe and effective malaria management products. Detailed summary of metal and metal oxide nanomaterials in malaria diagnosis and therapy was shown in Table 5.

Table 5. Summary of metal and metal oxide nanomaterials used for malaria diagnosis and therapy, along with their key findings.

2.5 Challenges and limitations of metal and metal-oxide nanoparticles in malaria control

Despite the considerable potential of metal and metal-oxide nanoparticles in malaria diagnosis, therapy, and vector control, there are several hurdles that hinder their clinical and field translation. Major limitations include dose-dependent cytotoxicity, environmental issues, poor colloidal stability, variability related to green synthesis, and lack of standardized regulatory frameworks (Nel et al., 2006; Iravani, 2011; Levard et al., 2012; Bobo et al., 2016; Fadeel et al., 2018).

2.5.1 Cytotoxicity and dose-dependent toxicity

The same physicochemical properties that render nanoparticles anti-parasitic through their high surface reactivity, ROS production, and metal ion release may cause mammalian cell toxicity following administration in higher concentrations. It has been shown that AgNPs are capable of causing dose-dependent cytotoxicity and genotoxicity through oxidative stress, mitochondrial dysfunction, apoptosis, and DNA damage, although green-synthesized AgNPs show less toxicity compared to chemically synthesized nanoparticles (Ali et al., 2022). Likewise, ZnO NPs may lead to oxidative stress, mitochondrial injury, and hepatotoxicity due to ROS production and Zn²⁺ ion release. While iron oxide nanoparticles and AuNPs are usually regarded as more biocompatible, increased iron release may initiate Fenton-like reactions, while ultrasmall or positively charged AuNPs may also be cytotoxic. In addition, toxicity is mainly studied on a few cell lines using short-term studies, emphasizing the need for comprehensive long-term safety evaluations (Avitabile et al., 2020).

2.5.2 Environmental impact

The use of metal and metal-oxide nanoparticles in environmental applications for vector control is associated with possible impacts of these substances on other living creatures and ecosystems in which these organisms live. AgNPs are the most explored nanoparticles in this context, and their transformation into other forms such as oxidation, aggregation, and sulfidation affects their environmental behavior and toxicity (Levard et al., 2012). While AgNPs and ZnO NPs are ecotoxic to aquatic microorganisms, algae, and invertebrates by releasing metal ions and producing ROS, Fe-oxides are considered to have relatively low environmental toxicity, and AuNPs are less acute toxins, though persistent in the environment (Eker et al., 2024; Bordin et al., 2024; Bordin et al., 2024). Despite promising larvicidal efficacy, many studies done on malaria are not detailed enough when it comes to non-pesticidal toxicity and persistence in the environment. This is especially true given that some AgNP larvicidal papers have been retracted. Thus, there is a need for standardized methods of assessing environmental risks before any nanoparticle-based vector control can be done.

2.5.3 Colloidal stability and aggregation in biological media

Colloidal stability is necessary for reproducibility in the development of nanoparticle-based malaria diagnosis, treatment, and vector control measures. Nevertheless, nanoparticles tend to aggregate within biological fluids owing to protein coating and variation in ionic strength, thereby leading to particle size variation, low availability of particles, rapid clearance from the body, and low efficacy of treatment and diagnostic methods. Also, storage in tropical settings, such as high temperatures and humidity levels, may further affect the stability of nanoparticles. Therefore, improving surface functionalization, formulation strategies, and storage stability will be essential for the successful clinical and field translation of nanoparticle-based malaria interventions (Mahmoudi et al., 2011; Monopoli et al., 2012; Albanese et al., 2012).

2.6 Carbon-based nanomaterials

Carbon-based nanomaterials have emerged as highly versatile platforms in nanomedicine because of their exceptional physicochemical, electrical, optical, and mechanical properties (Parvin et al., 2024). In malaria research, these materials have gained considerable attention for applications in biosensing, targeted drug delivery, imaging, and theranostics. Major classes of carbon-based nanomaterials include graphene and graphene oxide (GO), carbon nanotubes (CNTs), carbon dots (CDs), fullerenes, and nanodiamonds. Among these, graphene derivatives, CNTs, and CDs are the most extensively explored for malaria-related applications because of their large surface area, tunable surface chemistry, and multifunctional properties.

The exceptional conductive properties of graphene and CNTs due to the presence of highly delocalized π-electron systems make them ideal components for highly sensitive electrochemical biosensors that can detect biomarkers associated with malaria infection at very low concentrations (Parihar et al., 2025; Puttaningaiah, 2024; Ramoso et al., 2025; Channabasavana Hundi Puttaningaiah, 2024). The outstanding mechanical strength and stability of these materials contribute to improved performance and increased durability of the biosensors and drug delivery systems (Liao et al., 2026; Baruah et al., 2024; Bianco et al., 2005). In addition, due to their huge surface area, these nanomaterials help in the effective loading of antimalarial agents, antibodies, aptamers, nucleic acids, and other targeting ligands via hydrophobic interactions, electrostatic adsorption, covalent bonding, and π-stacking, hence increasing solubility, stability, bioavailability, and target delivery of drugs (Parveen et al., 2025). The carbon dots play an additional role by virtue of their tunable fluorescence and photostability properties, while graphene plays the role of effective fluorescence quenching, enabling sensitive imaging and fluorescence-based malaria diagnostics (Al Saidi et al., 2026; Lim et al., 2015).

2.6.1 Graphene and graphene oxide

Graphene and GO are among the most extensively studied carbon-based nanomaterials for malaria management due to their outstanding electronic conductivity, high surface area, flexibility, and modifiable surface chemistry. Graphene is made up of a one-atom-thick layer of sp²-bonded carbon atoms in a two-dimensional honeycomb structure, whereas GO possesses oxygenated groups such as hydroxyl, epoxy, and carboxyl groups, which render it dispersible in water and allow surface modification. The first study that highlighted the antimalarial potential of GO was carried out by Kenry et al., where it was shown that GO nanosheets efficiently suppressed the development of P. falciparum in vitro through merozoite invasion and delayed development of parasites from the ring into the trophozoite form (Kenry et al., 2017). The mechanism of action involves physical adsorption of merozoites by GO nanosheets and the removal of vital nutrients from the media, limiting the parasites’ growth. A study led by Castilho et al. showed that multilayer GO in the dry state has shown greater mosquito repulsion behaviors than controls, as shown in Figure 7 (Castilho et al., 2019). This study helps to prevent the mosquito bite prevention thereby avoiding the propagation of malaria. In dry states, graphene can avoid direct skin contact and avoid sensing skin- or sweat-related chemicals by mosquitoes. The high surface area and good biocompatibility of GO nanosheets have been suggested as suitable antiparasitic nanoplatforms based on the available reports.

Apart from their antimalarial properties, the graphene-based nanomaterials have exhibited outstanding promise in malaria diagnostic applications. The development of a graphene-based Surface Plasmon Resonance (SPR) biosensor by Wu et al. has resulted in 100-fold increase in the sensitivity of malaria DNA detection as compared to conventional optical biosensors, providing rapid and label-free detection of Plasmodium nucleic acids (Wu et al., 2020). In recent times, highly sensitive detection of Plasmodium falciparum lactate dehydrogenase (PfLDH) and stage-specific malaria infections was achieved using graphene-based electrochemical aptasensors, reduced Graphene Oxide (rGO) based FET biosensors, and hybrid terahertz (THz) sensing platforms, demonstrating the potential of graphene-enabled platforms for rapid point-of-care diagnosis and infection monitoring (Kumar et al., 2025; Figueroa-Miranda et al., 2022; Wekalao et al., 2025). Although there are various promising potential uses in therapy, diagnosis, and vector control, graphene-based nanomaterials may induce oxidative stress, membrane damage, inflammation, and genotoxicity depending on particle size, oxidation state, surface chemistry, and dose. So, optimization of surface functionalization and complete in vivo safety assessment remain needed for their successful clinical translation.

2.6.2 Carbon nanotubes

CNTs are cylindrical nanostructures composed of rolled graphene sheets and are categorized as single-walled CNTs (SWCNTs) or multi-walled CNTs (MWCNTs). CNTs possess extraordinary electrical conductivity, mechanical strength, thermal stability, and high aspect ratios, making them attractive for malaria biosensing and targeted drug-delivery applications.

Recent primary research demonstrates that CNTs provide highly sensitive platforms for malaria biomarker detection, particularly through their integration into electrochemical, chemiresistive, and field-effect transistor (FET) biosensors. A multi-walled carbon nanotube–zinc oxide (MWCNT–ZnO) nanofiber-based flexible chemiresistive biosensor was reported for label-free detection of malaria biomarker histidine-rich protein II (HRP2), achieving a broad detection range of 10 fg mL^-¹ to 10 ng mL^-¹ with high electrical sensitivity arising from charge-transfer modulation across the CNT network upon antigen binding, enabling rapid and low-cost detection suitable for point-of-care applications (Paul et al., 2017). As shown in Figure 8, the flexible sensing platform was constructed by depositing MWCNT-ZnO nanofibers between the source and drain electrodes patterned on a polyethylene terephthalate (PET) substrate. The sensor performance was evaluated by incubating the device with 10 μL of HRP2 antigen at varying concentrations for 30 min, followed by washing with PBS (pH 7.0), air-drying, and electrical resistance measurements. The specific binding of HRP2 to the functionalized nanofiber surface induced measurable changes in electrical resistance, enabling sensitive and quantitative detection of the malaria biomarker.

In another study, carbon nanofiber (CNF) forest-based immunosensors were developed for direct detection of PfHRP2, where dense antibody functionalization on CNF architectures produced strong signal amplification and enabled detection limits as low as 0.01 ng mL^-¹ (electrical readout) with rapid response times (~1 min), highlighting the exceptional surface-area-driven signal enhancement of carbon nanostructures for early malaria diagnosis (Gikunoo et al., 2014). In a recent study, CNT integration markedly enhanced electron-transfer kinetics and signal amplification, enabling highly sensitive detection of Plasmodium falciparum lactate dehydrogenase (PfLDH) in serum-like samples (Gikunoo et al., 2014). The CNT network provides a highly conductive, high–surface-area scaffold that facilitates dense immobilization of antibodies/aptamers, leading to ultralow detection limits, rapid response, and strong target selectivity. Notably, a CNT-based microfluidic electrochemical immunosensor targeting anti-PvMSP119 in human serum outperformed conventional ELISA, exhibiting higher sensitivity (lower LOD), improved precision (reduced RSD), and significantly reduced assay time (~2.5 h shorter) (Regiart et al., 2021). Mechanistically, this enhanced performance is attributed to one-dimensional charge transport along CNT networks and minimized interfacial electron-transfer resistance at the CNT–biointerface, which collectively amplify the electrochemical signal upon antigen–antibody binding.

Overall, these studies establish CNTs as robust nanotransducers for malaria diagnostics, offering ultrahigh sensitivity, rapid response, and compatibility with portable point-of-care devices, although further clinical validation and scalable manufacturing remain essential for translation into real-world malaria surveillance applications. Additionally, large-scale reproducible synthesis of CNTs with consistent physicochemical properties remains technically challenging. Variability in diameter, chirality, surface defects, and functionalization can significantly influence biological behavior and therapeutic performance. Therefore, rigorous purification, functionalization, and toxicity evaluation are necessary before CNT-based malaria nanotechnologies can progress toward clinical application.

2.6.3 Carbon dots

CDs are quasi-spherical 0D amorphous carbon nanoparticles generally smaller than 10 nm that exhibit unique fluorescence and photoluminescent properties. CDs have attracted growing interest in malaria nanotechnology because of their excellent aqueous solubility, low toxicity, photostability, facile synthesis, and tunable optical behavior. One of the most important applications of CDs in malaria control is their use as fluorescent probes for rapid malaria detection. Their excitation-dependent fluorescence, high photostability, and ease of surface functionalization make them highly suitable for detection of malaria biomarkers such as parasite DNA, proteins, hemozoin, and metabolites. Surface functionalization with biomolecules like antibodies, aptamers, nucleic acids, or targeting ligands improves their specificity toward Plasmodium biomarkers. For instance, Singh et al. developed a CD-coupled aptamer biosensor for the detection of Plasmodium falciparum glutamate dehydrogenase (PfGDH), an important malaria biomarker shown in Figure 9, using a highly specific ssDNA aptamer (NG3). CD–aptamer complexes bind to PfGDH, showing enhanced fluorescence for sensitive biomarker detection. The biosensor has a linear range of 0.5–25 nM and an LOD of 0.48 nM, with 2.85 nM in diluted serum. This indicates that carbon dot-based biosensors are effective for rapid and specific malaria diagnosis, suggesting their use as cost-effective point-of-care diagnostics in malaria-endemic areas (Singh et al., 2018).

In another study, Nitrogen-doped CDs (N-CDs) have also been used as fluorescent probes for imaging Plasmodium falciparum–infected red blood cells (Xu J. et al., 2022). Due to malaria-induced new permeability pathways, N-CDs are preferentially internalized by infected erythrocytes, while showing minimal uptake in healthy cells, enabling high-contrast discrimination of infection. This selective accumulation allows real-time fluorescence imaging of live parasites without affecting cell viability. Mechanistically, the strong photoluminescence, nanoscale size, and surface functionality of N-CDs facilitate efficient cellular entry and stable intracellular imaging with minimal photobleaching. Beyond diagnostics, the CDs have found another useful biomedical application as nanocarriers in antimalarial drug delivery. Recent developments have further broadened the use of CDs for paper and lateral flow assay formats, which allow for quick detection of malaria markers using CDs conjugated with antibodies or DNA via fluorescence analysis requiring little sample preparation. In addition, heteroatoms-doped CDs (for example, N- and S-doped CDs) offer increased quantum yield and target affinity, thus making the detection of malaria markers by biosensors more sensitive and selective (Zhang et al., 2021; Sun et al., 2019).

Apart from CDs, graphene quantum dots (GQDs) are the same class of nanomaterials with crystallinity and a 2D structure. Due to their smaller size (2–20 nm) and fluorescence properties similar to those of CDs, we have brought the discussion of this novel material into this CDs section. Torkashvand et al. formulated GQD-based formulations to co-deliver antimalarial drugs artesunate and mefloquine to P. falciparum (Torkashvand et al., 2023). They obtained a sustained release of drugs (>90%) in 36 hours, better antiplasmodial activity, and increased biocompatibility in the GQD formulation. The combined GQD-artesunate-mefloquine formulation exhibited higher efficacy (IC₅₀ = 3.6 μg/mL) than the single-drug formulations, underscoring the potential of CDs for improving antimalarial therapy. A detailed summary of carbon-based nanomaterials in malaria diagnosis and therapy is shown in Table 6.

Table 6. Summary of carbon-based nanomaterials used for malaria diagnosis and therapy.

2.6.4 Challenges

Although they have been shown to have significant potential in malaria diagnosis and treatment, carbon nanomaterials encounter a number of barriers that make it difficult for them to be clinically translated. Their biocompatibility has been a critical problem, especially CNTs, as well as some graphene materials, which can cause oxidative stress, inflammation, fibrosis, membrane disruption, and mitochondrial dysfunction depending on their physicochemical properties (Yuan et al., 2019; Duke and Bonner, 2018; Xiaoli et al., 2021). Furthermore, the slow rate of biodegradation coupled with their tissue persistence makes it possible for carbon nanomaterials to accumulate in major organs, which necessitates better biodegradability and biocompatibility (Xie et al., 2017; Yang et al., 2012).

It is still difficult to synthesize large quantities of materials with homogeneous morphology, purity, and surface chemistry, while variations in batches may greatly influence the physical and biological properties of carbon nanoparticles. Moreover, the aggregation of nanoparticles in the physiological environment will lower their colloidal stability, bioavailability, targetability, and diagnostic efficacy. Further studies should be devoted to the scalable and repeatable synthesis, thorough examination of pharmacokinetics, biodistribution, biodegradability, toxic effects, and safety, as well as the creation of multicomponent carbon nanoparticle platforms for the safe diagnosis and treatment of malaria.

3 Polymeric and lipid nanocarriers

Polymeric and lipid-based nanocarriers have become one of the most versatile drug delivery systems because of their great biocompatibility, biodegradability, and ability to improve the pharmacokinetic and therapeutic properties of encapsulated drugs. These colloidal drug delivery systems, which are typically from 1 to 1000 nanometers in size, have revolutionized the field of nanomedicine by addressing many of the problems that exist in traditional drug delivery systems such as poor aqueous solubility, rapid metabolism, low bioavailability, and toxicity at high doses (Din et al., 2017; Lu et al., 2021). In malaria treatment, these polymeric and lipid-based nano-systems have been employed as carriers for antimalarials, including chloroquine, quinine, and artemisinin derivatives. Their ability to encapsulate drugs, protect them from degradation, enhance aqueous solubility, extend blood circulation time, and enable controlled or targeted drug delivery enhances therapeutic efficacy while reducing systemic toxicity (Thu et al., 2017; Ma et al., 2014; Nwagwu et al., 2026; Shakeel et al., 2019). Moreover, these nanocarriers offer advantageous strategies to tackle the problems associated with malaria management, including multidrug resistance and suboptimal pharmacokinetics of drugs. These nanocarriers can improve drug concentrations at the target site and sustain its level over a period of time by modifying the biodistribution and release kinetics of encapsulated drugs, thereby reducing dosing frequency and minimizing adverse effects (Hirayama et al., 2021; Bagheri et al., 2017; Sato et al., 2024). The following sections summarize the advances made in designing polymeric and lipid nanoparticles for malaria treatment.

Structurally, nanocarriers differ in their physical state, assembly mechanisms and internal matrix organization. Liposomes consist of fluid, concentric phospholipid bilayers wrapping around an isolated aqueous core, permitting simultaneous dual encapsulation of hydrophilic and lipophilic payloads (Mhlwatika and Aderibigbe, 2018). Solid lipid nanoparticles feature a rigid, highly ordered crystalline lipid core that offers protection against degradation but can trigger lattice drug expulsion during shelf storage (Priya et al., 2023). To resolve this rigidity, nanostructured lipid carriers blend solid lipid and liquid lipids to create a spatially disrupted, amorphous matrix with higher drug capacity and minimal expulsion. Polymeric nanoparticles consist of dense, solid polymer beads or solid shell-enclosed liquid capsules that deliver high mechanical durability and slow hydrolysis-driven release kinetics (Kenechukwu et al., 2025).

3.1 Polymeric nanoparticles (polymer-based nanocarriers)

Polymer nanoparticles represent one of the most promising nanocarriers for malaria treatment due to high biocompatibility, biodegradability, stability, and their ability to deliver drugs in a controlled manner (Patra et al., 2021). They are usually made from natural polymers like chitosan and gelatin or synthetic biodegradable polymers like poly(lactic-co-glycolic acid) (PLGA) and polylactic acid (PLA), and their physicochemical characteristics can be customized to enhance drug loading, release, circulation, and treatment efficiency (Bhargava et al., 2024). Nanoparticles made from polymers can structurally be categorized into micellar nanospheres, wherein the drugs are homogeneously distributed within the matrix, and nano-capsules, wherein the drugs are encapsulated inside the polymeric matrix (Bhargava et al., 2024). After their administration, these systems degrade gradually and release the drugs over time to maintain therapeutic concentrations in the plasma for extended durations while reducing dosing frequency and systemic toxicity (Mhlwatika and Aderibigbe, 2018).

Recently, several studies have shown that polymeric nanoparticles have the potential to be active antimalarial nanomedicines rather than simply drug carriers. For instance, Hamelmann et al. synthesized single-chain polymer nanoparticles (SCNPs), which had a selective effect on the ookinete stage of Plasmodium berghei in the mosquito midgut, leading to reduced parasite survival and transmission without compromising mosquito viability (Hamelmann et al., 2023; Najer et al., 2024). This study is one of the few demonstrating the possibility of interfering with parasite development in the mosquito vector using rationally designed polymeric nanoparticles. However, targeting the parasite within the mosquito midgut presents significant logistical hurdles for real-world deployment, as delivering these nanoparticles effectively to wild vector populations remains practically unfeasible. Furthermore, the study lacks long-term ecotoxicological evaluations regarding the environmental persistence and safety of these synthetic SCNPs in aquatic vector breeding habitats. Another recent study, methoxybenzenesulfonate-functionalized biopolymer nanoparticles exhibited enhanced activity against malaria and sequestration by preventing the cytoadherence of parasitized red blood cells, thus causing reduced inflammation in severe malaria without compromising their anti-parasitic activity, suggesting that polymer surface engineering can simultaneously improve antiparasitic efficacy and mitigate malaria pathogenesis (Najer et al., 2024). These results show that polymeric nanoparticles are developing from mere drug carriers into multifunctional therapeutic platforms capable of targeting multiple stages of malaria infection. Nevertheless, the primary drawback of this strategy lies in the highly complex, multi-step surface functionalization chemistry required to attach the methoxybenzenesulfonate groups. This chemical complexity introduces substantial batch-to-batch variability and limits the scalability of the formulations for industrial manufacturing. It is not discussed thoroughly regarding the potential risks of chronic accumulation or the long-term degradation kinetics of these functionalized biopolymers in clearance organs like the liver and spleen.

In addition to the intrinsically active agents, considerable attention has been paid to the use of polymeric nanoparticles for loading standard antimalarial agents such as chloroquine, quinine, artesunate, artemisinin-based agents, and other poorly soluble antimalarials. Loading of drugs into degradable polymeric matrices is useful for increasing their water solubility, protecting from degradation, increasing the circulation time, and providing controlled and sustained release, which increases the bioavailability of drugs and decreases dose-dependent toxicities. Recently, surface-modified polymeric nanoparticles were studied in order to increase the parasite-targeting ability, overcome the problem of multidrug resistance, and increase the intracellular loading of antimalarial agents (Heidari et al., 2022; Assawapanumat et al., 2025; Najafzadeh et al., 2022; Lu et al., 2021). Anjani et al. had synthesized a hydrogel for transdermal delivery of drugs to inhibit the parasite during its blood stage and had shown some promising results (Figure 10) (Anjani et al., 2026). A recurring limitation across these standard encapsulation studies is the widespread reliance on toxic organic solvents during synthesis. Incomplete solvent removal poses severe safety risks, and many of these formulations suffer from an initial, uncontrolled “burst release” phase where a substantial portion of the drug payload leaks out into the plasma before the nanocarriers can successfully reach intraerythrocytic target sites.

Different polymeric architectures have further expanded the scope of therapeutic applications. For instance, polymeric micelles represent self-assembly structures synthesized from amphiphilic block copolymers, which effectively load antimalarials into their core with hydrophobic drugs and increase blood circulation and stability through hydrophilic shells (Lu et al., 2021; Patra et al., 2021). The main shortcoming of micellar systems is their relatively low thermodynamic stability upon extreme dilution in the bloodstream, which can cause the micelles to prematurely disassemble below their critical micelle concentration (CMC) and dump their cargo off target. The dendrimers are known for their highly branched 3D structures with lots of cavities and surface groups that facilitate high drug loading ability as well as attachment of various functional groups at a time for the development of multifunctional malaria therapies (Lu et al., 2021). However, high-generation dendrimers frequently exhibit pronounced, dose-dependent cytotoxicity and hemolytic activity due to their highly charged surface groups, and their clinical translation is severely constrained by prohibitive manufacturing costs. The hydrogels, due to their crosslinked polymer network and stimuli-responsiveness, have also been used for delivering antimalarial drugs in a localized manner by responding to physiologically induced stimuli like p^H and temperature (Owonubi et al., 2018; Cortes et al., 2019).Yet hydrogel delivery systems face significant translational gaps in malarial management because their macro-scale structural properties restrict them primarily to localized or transdermal applications, rendering them poorly suited for rapid systemic interventions required during acute, life-threatening parasitemia.

Collectively, polymeric nanocarriers are versatile tools that can be used to enhance the pharmacokinetic properties, effectiveness, and safety of antimalarial drugs. Future improvements in biodegradable polymers, surface modifications, and stimul-responsive nanocarriers will contribute to the development of multicomponent polymer formulations for delivery, transmission inhibition, and immune modulation in the future generation of malaria treatment. Table 7 summarizes some more polymeric nanoparticles and lipid-based nanocarriers alongside their efficacy.

Table 7. Advanced polymeric and lipid-based drug delivery systems for malaria control, emphasizing the surface functionalization strategies utilized to achieve targeted delivery, stage-specificity, or controlled release.

3.2 Lipid-based nanocarriers

These nanocarriers are easily able to interact with cell membranes as they are made up of physiological lipids, enabling intracellular delivery of antimalarial drugs while increasing the solubility and bioavailability of poorly soluble drugs. Furthermore, they prevent any premature degradation of the drugs that have been enclosed and promote their systemic circulation while also ensuring controlled delivery of the drugs, thereby enhancing therapeutic efficacy and reducing systemic toxicity. Based on their arrangement, lipid-based nano-delivery systems can be divided into two groups, namely vesicular systems like liposomes and niosomes and non-vesicular systems such as SLNs and NLCs (Lu et al., 2021; Priya et al., 2023). he major lipid-based nanocarrier platforms currently investigated for antimalarial drug delivery are illustrated in Figure 11. These systems differ in lipid composition, structural organization, drug loading mechanisms, and therapeutic applications, thereby, offering distinguished advantages for improving the pharmacokinetics and therapeutic efficacy of antimalarial agents.

Liposomes are the oldest and most thoroughly studied nanocarriers using lipid-based nanotechnology for malaria chemotherapy. These vesicles consist of one or more layers of phospholipids enclosing an inner water layer, hence making it possible to encapsulate drugs which are both hydrophobic and hydrophilic (Lu et al., 2021; Priya et al., 2023). The biomimetic nature of the membrane allows easy fusion with cell membranes and protection of drugs against enzymatic degradation, and improves intracellular delivery to infected erythrocytes. It is well established that liposomes have shown immense promise in enhancing the pharmacokinetic profile of various antimalarial drugs (Memvanga and Nkanga, 2021). For instance, Zeng et al. developed a liposomal formulation for decoquinate (DQ), an effective multistage antimalarial drug with poor aqueous solubility. The DQ-loaded liposomes demonstrated a particle size around 150 nm, high encapsulation efficiency of the drug more than 95%, good storage stability, and negligible cytotoxicity; while effectively suppressing Plasmodium berghei infection upon intravenous administration (Zeng et al., 2022). This study demonstrates that liposomal encapsulation is effective in overcoming formulation problems of very hydrophobic antimalarial compounds. A prominent limitation of this formulation is its absolute reliance on intravenous administration, which severely restricts its utility in remote, resource-limited field clinics where sterile injectable infrastructure is absent. Moreover, the study did not evaluate the physical stability of liposomal suspension when exposed to the high temperatures and high humidity typical of malaria-endemic tropical environments, conditions that rapidly accelerate lipid oxidation and leakage.

In addition to serving as carriers of individual drugs, liposomes have also been investigated for dual therapy as well as targeted delivery of drugs. In order to enhance targeted delivery of antimalarial drug combinations, Biosca et al. have designed immunoliposomes by antibody functionalization that help achieve specific parasitic targeting while decreasing any off-target toxicity (Biosca et al., 2019). Such nanovector systems are useful because they allow for coordinated administration of rapidly acting derivatives of artemisinin along with slowly acting drugs. This may enhance therapeutic success while preventing the development of resistance to the drugs used (Nwagwu et al., 2026). Recent reports further underscore liposomes as promising multifunctional platforms capable of integrating targeted drug delivery, vaccine development, and immunomodulation for next-generation malaria management (Memvanga and Nkanga, 2021). Despite the elegance of this dual-delivery approach, the primary shortcoming lies in the rapid biological formation of a “protein corona” once introduced into the blood plasma. This protein layer physically shields and masks the surface-bound antibodies, severely impairing the targeting efficiency of the liposomes. Additionally, the exorbitant cost and fragile stability of monoclonal antibodies make these immunoliposomes economically unviable for mass distribution in public health sectors.

Niosomes are nano-carriers that are structurally similar to liposomes, except that they are made from non-ionic surfactant stabilizers and cholesterol rather than phospholipids, which makes them much more stable and economical to produce (Oyeyemi et al., 2018). Niosomes are able to encapsulate hydrophilic and hydrophobic antimalarials in an effective manner with sustained drug release and increased stability in tropical climates. Even though niosomes hold considerable promise for increasing bioavailability of drugs as well as decreasing toxicity levels, their use in the case of malaria is not as advanced as liposome-based delivery systems. The main technical drawback of niosomal carriers is their high propensity for physical aggregation, leakage, and fusion during long term storage, which causes erratic drug release profiles and unpredictable shelf lives under field conditions. However, recent studies consider niosomes as emerging lipid-based platforms with great potential for future antimalarial drug delivery, particularly for resource-limited settings where formulation stability and manufacturing costs are critical (Miatmoko et al., 2024).

Solid lipid nanoparticles (SLNs) were developed as an alternative to liposomes to increase the stability of lipid systems while delivering drugs under control. These particles contain biocompatible lipids that are in solid form at both ambient and physiological conditions, creating matrices that are stable and can provide protection against drug degradation due to chemical and enzymatic reactions (Mhlwatika and Aderibigbe, 2018). Drugs contained within the solid lipid matrix get released through diffusion and hydrolysis of lipids, thus increasing circulation time and ensuring sufficient drug concentration in the blood (Patra et al., 2021; Nwagwu et al., 2026). It has been shown recently that SLNs enhance solubility, bioavailability, and sustained release of insoluble antimalarial drugs, as well as reduce their toxicity, thus becoming potential drug carriers for long-term malaria treatment (Vassoudevane et al., 2023; Valissery et al., 2020). The core limitation of this platform is its highly crystalline, perfect solid lipid lattice structure. Over time, this lattice undergoes polymorphic transitions into a more stable crystalline state, resulting in a low overall drug loading capacity and the spontaneous expulsion of the encapsulated antimalarial agent during storage.

Nanostructured Lipid Carriers (NLCs) are the second generation of lipid nanoparticles and were invented to address the problem of low loading capacity and drug release of SLNs. They are made up of a combination of solid lipids and liquid lipids to create an incomplete lipid matrix that allows higher drug loadings while maintaining greater formulation stability (Mhlwatika and Aderibigbe, 2018). Compared to SLNs, NLCs show enhanced entrapment efficiency, increased storage stability, and biphasic drug release patterns, which ensure an immediate pharmacological effect along with prolonged retention of effective drug concentrations (Nwagwu et al., 2026). It has been established from recent studies that NLCs increase the bioavailability of poorly soluble anti-malaria drugs and serve as flexible platforms for surface modifications and targeted drug delivery (Akpa et al., 2020). However, a recurring deficit in NLC research for malaria is the lack of extensive, long-term safety profiles regarding the toxicity of the liquid components. Many studies focus heavily on short-term efficacy in rodent models, completely omitting thorough investigations into chronic tissue accumulation, systemic clearance kinetics, and the potential for triggering inflammatory responses in host tissues upon repeated dosing.

Overall, lipid-based nanocarriers have proven to be highly flexible carriers that could enhance the pharmacokinetics and effectiveness of antimalarial agents as well as increase their safety. The high biocompatibility of these nanoparticles, along with their high capacity to encapsulate various drugs and controlled targeted drug release, could contribute to overcoming problems such as low solubility of drugs, multidrug resistance, and toxicity of treatment. Further studies should address large-scale production, stability, targeted surface modification, and preclinical and clinical testing.

3.3 Functionalization strategies

Surface modification has proven to be an effective approach for enhancing targeting ability and effectiveness of antimalarial drugs loaded within lipid nanoparticles. The surface modification of nanoparticles through conjugation of targeting molecules on their surface results in significant improvement in the selective delivery of antimalarial drugs to infected red blood cells and intracellular parasites. Marques et al. synthesized glycophorin A-targeted immunoliposomes containing both pyronaridine and atovaquone, which selectively targeted Plasmodium falciparum-infected red blood cells and gametocytes and showed strong antiplasmodial activity with very low concentrations of the drugs and little cytotoxicity (Moles et al., 2015). However, a key limitation of targeting glycophorin A is that it is also heavily expressed on healthy erythrocytes, significantly increasing the risk of off-target accumulation and unintended lysis of non-infected red blood cells.

In another study, heparin-coated cationic liposomes were used to deliver the drug primaquine specifically to infected erythrocytes with about three times more antiplasmodium activity than primaquine alone at concentrations below the threshold for anticoagulation (Marques et al., 2017). Despite the increased activity, the primary disadvantage of heparin functionalization is the strict requirement to keep concentrations below the anticoagulation threshold, narrowing the therapeutic window and creating substantial risks of internal bleeding if dosing is not perfectly controlled. Lipid nanoparticles that respond to stimuli have also been proven highly promising. Vyas et al. created pH-responsive liposomes using destabilizers such as oleyl alcohol to deliver the antigen PfMSP-1₁₉ of malaria into the cells. The release of this antigen inside acidic vesicles increased its efficacy in mice, proving the use of functionalized liposomes for malaria vaccine development (Vyas et al., 2008). Nevertheless, pH-responsive liposomes are often limited by premature leakage in slightly acidic microenvironments outside the target cells, and the addition of destabilizing components like oleyl alcohol can negatively impact the overall shelf life and physical stability of the formulation.

3.4 Challenges and future perspectives

Although substantial progress has been made, a number of obstacles persist in the clinical implementation of lipid-based nanocarriers as a treatment of choice against malaria. Drug release at an early stage of circulation can affect treatment effectiveness before delivery of nanomaterials to parasitized red blood cells. Moreover, binding of plasma proteins to nanoparticle surface results in the development of a protein corona that hinders targeting ligands, changes the distribution pattern of nanomaterials, and increases their removal by the mononuclear phagocyte system (Xu W. et al., 2022). Manufacturing is also difficult because the production of sterile and reproducible lipids in bulk form involves advanced technological processes and stringent quality checks. Moreover, stability during long-term storage at high temperatures typical of the malaria-prone regions poses a challenge. The future direction of research should therefore be in ensuring that there are improvements in terms of formulation stability, reduction of protein corona, scalability in manufacturing and evaluation.

4 Artificial intelligence for malaria control

The recent advancements in software and hardware technology have made a remarkable impact in diversified fields, especially in medicine. AI and machine learning-based integrated systems have made a malaria diagnostic workflow very simple, accurate, and rapid. It helps to compile the data obtained from a pinch of blood and produce highly valuable information related to clinical symptom assessment and the hematological profile of the patient. The microscopy analysis integrated with AI-powered machine learning tools and real-time analysis based on rapid detection kits and smartphone sensors, including artificial neural networks (ANNs) and convolutional neural networks (CNNs), can help AI to help to identify the type of Plasmodium-infected erythrocytes and their related stages, helps for the accurrately provide therapy to the patient. It helps the time to reduce and limit therapy to shorter dosages if detected in early stages and hence stops prolonged therapy. The AI-integrated smart database could also help to monitor the disease history and remote access of the data from hospital to hospital. It also helps to provide age-, gender-, and living circumstances-based treatment with the highest accuracy and helps to give a personalized medicine. The medicine integrated with intelligent AI systems can strengthen malaria monitoring and control at a fast pace in the world as the mortality rates increase every year. (Aqeel et al., 2023; Gaouar et al., 2025; Obeagu and Ogenyi, 2025). Figure 12 shows the systematic malaria diagnosis process (microscopic, mobile-based, and rapid diagnostic kits) based on AI-powered computer vision and machine learning methods associated with ANN and CNN intelligent model technology. Though the AI integration is in nacent in stage, we are anticipating that it could make a remarkable revolution by providing a smart theranostic process.

5 Conclusion and future perspectives

Malaria remains a significant global health issue, even with progress in treatment, vector control, and vaccination. The quick rise of multidrug-resistant Plasmodium strains, insecticide-resistant Anopheles mosquitoes, and the shortcomings of standard diagnostic and treatment methods highlight the pressing need for new intervention strategies. This review shows that nanotechnology provides a flexible platform for tackling many of these problems through better diagnosis, targeted drug delivery, improved drug absorption, vaccine development, and integrated vector management. Among the different nanomaterials discussed, metal and metal oxide nanoparticles have multiple roles in detecting parasites, targeted therapy, magnetic separation, and mosquito control. Carbon-based nanomaterials offer highly sensitive biosensing platforms and multifunctional drug delivery systems due to their excellent electrical, optical, and surface properties. Polymeric and lipid-based nanocarriers have shown great potential to increase the effectiveness, stability, and controlled release of antimalarial drugs while minimizing systemic toxicity. Together, these nanoplatforms represent promising next-generation solutions that can address several challenges in traditional malaria management.

Despite these encouraging developments, it is important to note that the majority of nanotechnology-based antimalarial approaches are still at the stage of concept validation and preclinical trials. There are some major issues preventing these approaches from being used in clinics, such as variability in synthesis methods, lack of physicochemical standardization, possible toxic effects after long-term exposure, biodistribution and pharmacokinetics questions, scalability, licensing and manufacturing issues, and cost-effective large-scale production. In addition, there are numerous reports showing results only in in vitro studies or small animals, while more extensive clinical evaluation in the malaria model is needed. Future research must be directed toward the rational development of multifunctional and responsive nanosystems with an ability to combine diagnostic, targeted therapy, immunomodulatory, and therapeutic monitoring features into one platform. Such hybrid nanocomposites, which will merge the unique properties of metal-based, carbonaceous, polymer-based, and liposomal nanocarriers, could bring synergetic advances in terms of enhanced therapeutic activity, target specificity, and safety. The combination of artificial intelligence and machine learning approaches with nanomedicine may facilitate the development of new nanoparticles and help to optimize formulations, predict bioactivity, and develop personalized medicine approaches. Simultaneously, advancements in green nanoparticle synthesis, biomimetic surface modification, and precision medicine could contribute to this aim.

New technologies that include CRISPR-based biosensors, wearable diagnostics, paper microfluidic devices, and point-of-care nanodiagnosis provide more possibilities for rapid and affordable monitoring of malaria, especially in low-resource areas. In addition, by integrating nanotechnology into already available treatments, including artemisinin-based therapy, monoclonal antibodies, transmission-blocking vaccines, and vector management programs, a synergistic approach can be developed to mitigate the disease and postpone the development of drug resistance. Overall, the application of nanotechnology has the potential to revolutionize malaria theranostics through the early detection of the disease, efficient delivery of drugs, high therapeutic effectiveness, and comprehensive disease management. Interdisciplinary cooperation between the different scientific disciplines mentioned above will be vital for the further development of these innovative discoveries from the laboratory stage into practical clinical applications.

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Footnotes

Edited by: Mariah Hassert, The University of Iowa, United States

Reviewed by: Prasoon Madhukar, Banaras Hindu University, India

Ebrahim Abbasi, Shiraz University of Medical Sciences, Iran