Advancements in polymer- and lipid-based nanoparticles for enhancing drug solubility, stability, and bioavailability: an integrative and forward-looking review

1 Introduction

The progression of the drug candidate through preclinical discovery to clinical development has continued to pose a challenge in the pharmaceutical development process, largely because of poor physicochemical and biopharmaceutical characteristics of compounds (Hashmi et al., 2025). Limited aqueous solubility, chemical instability, and oral bioavailability often compromise therapeutic performance and add to differences in clinical outcome variability. Assessment of the latest trends in drug-approval reports by regulatory authorities shows that a small percentage of new drugs approved have solubility and permeability profiles that are suitable for conventional dosage formulations, with most being able to be formulated only by more sophisticated dosage techniques to achieve an acceptable systemic exposure (Homayun et al., 2019).

These restrictions are most evident with the compounds that are discovered using modern high-throughput screening and structure-based drug design methods. This type of methodology is used for molecules of the Biopharmaceutics Classification System (BCS) II and IV, which have low solubility or permeability (Ekhator et al., 2023). This leads to erratic gastrointestinal absorption, inappropriate pharmacokinetics, heightened dosing need, and excessive interindividual variability. These risks increase potential side effects and add significantly to late-stage development failure (De et al., 2025).

Conventional formulation systems tend to be incapable of overcoming these challenges because they can be linked to physical and chemical instability, deficiency of regulated drug delivery, oxidative degradation, and fast drug precipitation during dilution. The deficiencies have increased the need for improved drug delivery systems (DDSs) that would offer better solubility, stability, and bioavailability, while retaining scalability and regulatory acceptability (Wilar et al., 2024). DDSs based on nanoparticles (NPs) are a potential solution to these multifaceted challenges. Drug dissolution behavior, labile compounds, absorption, and biodistribution can be altered by controlling carrier properties at the nanoscale, preventing labile compounds from degrading, and allowing controlled or targeted release of drugs (Vega-Vásquez et al., 2020).

Several nanocarrier platforms are available. Polymer- and lipid-based nanoparticles have been studied extensively because of their biocompatibility, freedom of formulation, and growing clinical relevance (Giordano et al., 2024). The systems have complementary but different benefits, such as programmable material composition, effective uptake by cells, functionalization of surfaces, and compatibility with a broad scope of therapeutic cargo, including small molecules up to nucleic acids. With these platforms, considerable progress has been achieved in sustained drug delivery (DD), lymphatic targeting, and nucleic acid-based therapies, further showing how formulation design can have a direct effect on pharmacokinetic behavior and therapeutic efficacy (Uti et al., 2025). Several products obtained based on such systems have been granted regulatory approval, which underscores their translational potential (Rachamala, 2025).

This review focuses on polymer- and lipid-based nanoparticles due to their maturity for clinical translation, scalability in manufacturing, and familiarity within regulatory frameworks compared with many inorganic or metallic nanocarriers (Viegas et al., 2023). Lipid-based nanoparticle systems have exhibited a solubility enhancement of approximately 5–50 times for those drugs that scarcely dissolve in water and an increased absorption of approximately 2–10 times. Likewise, amorphous stabilization, nanoscale dispersion, and controlled release have demonstrated 3–20 times and 1.5–8 times increases in dissolution rate and bioavailability, respectively, of polymeric nanoparticle formulations. Although these values are diverse, depending upon drug properties and formulation design, these reported ranges indicate the large quantitative effects of nanocarrier-based approaches to traditional formulations. Having a wide adoption of development in pharmaceuticals, such a system plays an important role in guiding formulation decision-making and developing therapeutic approaches (Wu et al., 2024).

Although the research on nanoparticle-mediated drug delivery has been growing rapidly, the current literature remains fragmented. Current reviews often focus on individual carrier types, a particular therapeutic use, or a method of material synthesis, and sometimes do not provide a comparative evaluation of the key types of platforms. Consequently, complementary design principles, translational issues, and regulatory concerns of polymeric and lipid-based nanoparticles are not found in a single framework. New hybrid lipid/polymer nanostructures and structured decision-making models of carrier selection have yet to be synthesized.

To overcome these drawbacks, this review offers a systematic and comparative analysis of polymer- and lipid-based nanoparticle systems that should be used to improve drug solubility and bioavailability. Unlike prior reviews, this review article incorporates physicochemical design toward the biopharmaceutical performance and clinical translation viewpoint. It focuses on formulation-based decision-making, talks about the developments in hybrid architectures, and considers the real-world issues associated with scalability, manufacturability, and regulatory acceptability. The proposed review will fill a gap between traditionally separated perspectives in the materials science, pharmaceutics, extracts, and nanomedicine fields by offering a structured and application-oriented information source to formulation scientists and translational researchers.

1.1 Search process

A systematic search of the literature was conducted in the major scientific databases, such as PubMed, Scopus, Web of Science, and Google Scholar. These helped cover key findings clearly. Articles published between 2010 and 2025 were filtered based on keyword combinations associated with polymeric nanoparticles, drug solubility, lipid-based nanoparticles, improvement of bioavailability, types, and nanocarrier drug delivery. There was a focus on peer-reviewed original research, reviews, and translation research, which provided mechanistic information or comparative formulation analysis. The literature on quantitative evidence is also a step toward explaining the extent to which nanoparticle formulations can enhance drug performance.

2 Fundamentals of solubility, stability, and bioavailability

2.1 Interdependence of solubility, stability, and bioavailability

These are unique but inseparable properties that combine to define therapeutic performance. A compound may exhibit poor solubility, which may limit its ability to reach its site of absorption, and chemical or physical instability may decrease effective systemic exposure despite absorption. On the other hand, the formulation strategies that focus on solubility improvement (amorphization or molecular dispersion) can, unwillingly, interfere with the drug stability (Chen et al., 2025). Such interdependencies may be in the form of synergy or antagonism, and hence, there is a need to appreciate the dynamic nature of their interaction during formulation development.

Studies by Langer and others have shown that the addition of anticancer agents with low solubility in water, for example, paclitaxel, into polymer carriers led to significant enhancement of apparent solubility due to their dispersibility in polymer matrices (Hiremath et al., 2013). The produced amorphous form, however, was proven to be less stable than the crystalline one, and it tends to recrystallize during storage, thus affecting its stability and release behavior (Ma, 2013). Later research, such as that by Torchilin, demonstrated that confinement of nanoscale and carrier-mediated amorphization of chemical compounds such as curcumin not only increases the rate of dissolution but also influences chemical stability and pharmacokinetics in vivo.

These results, in combination, indicate that solubility enhancement strategies in nanoparticle systems inevitably affect several interdependent properties. Conventionally, solubilization, stability, and bioavailability have been optimized as individual parameters in the formulation design process. However, the study of nanoscale systems has revealed that these properties are actually an interlinked system, as opposed to individual parameters. This has challenged the reductionist formulation approach and has underscored the need to adopt a holistic approach in lipid and polymeric nanocarrier systems.

These mutually dependent attributes not only exist as theoretical entities but have also been exemplified by clinically approved nanomedicines, such as the liposomes used in Doxil® and AmBisome®, as well as the lipid particles used in the mRNA COVID-19 vaccines, which exemplify the importance of solubility, stability, and bioavailability in the successful treatment of diseases.

2.2 Solubility enhancement at the nanoscale

Apparent drug solubility is enhanced at the nanoscale by several complementary interactions, such as surface area, decrease in diffusion distance, nanoconfinement, and desirable drug-carrier interactions (Liu et al., 2024). Drugs are frequently stabilized in an amorphous or molecularly dispersed form by polymeric nanoparticles, resulting in a faster rate of dissolution and higher apparent solubility.

In contrast, lipid-based nanoparticles have a greater effect on solubilization by virtue of the partition effect of the drug into lipid matrices and the generation of mixed micelles during gastrointestinal digestion, which is especially important in the case of oral delivery (Fatima et al., 2025). Note that the solubility observed as a result of encapsulation of the nanoparticles cannot always be equated with the actual thermodynamic solubility. Rather, it is a kinetically stabilized condition, which might be sensitive to the composition of the formulations, storage conditions, and physiological conditions. These factors must be taken into consideration when examining the dissolution and solubility data of nanoparticle systems (Zhang et al., 2023).

In contrast to classical methods such as oxidation, salt formation, or solvency, which improve solubility at a minimum or limited stage, using a nano system improves carrier interactions and transient supersaturated states. This distinction highlights a fundamental shift from equilibrium-based solubility enhancement toward system-dependent solubilization strategies, thereby necessitating revised evaluation frameworks. Importantly, these dynamic states may also introduce new stability considerations unique to nanoscale architectures.

2.3 Stability

Drug stability can be discussed as chemical breakdown mechanisms, physical alterations, including crystallization or aggregation, and biological instability, which is a result of enzymatic metabolism (Zhang et al., 2023). Nanoparticle carriers can offer physical barriers and controlled microenvironments to encapsulate drugs and protect them against hydrolysis and oxidation, photodegradation, and enzymatic attack (Poovi and Damodharan, 2018).

New instability mechanisms might also arise as a result of a nanoscale delivery system, the release of drugs by polymer degradation, lipid polymorphic phase transitions, or leakage of payload during storage (Hidayat et al., 2025). This has necessitated that stability evaluation of nanoparticle formulations to go beyond traditional shelf-life evaluation and include dynamic fluctuations in the formulation during the manufacturing process, storage, and in vivo exposure. These stability considerations need a thorough comprehension to secure uniform performance and clinical reliability.

2.4 Biological and physiological barriers

Bioavailability is influenced by biological and physiological barriers such as mucus diffusion limitations, efflux transporters, epithelial permeability constraints, enzymatic breakdown, and pre-systemic metabolism. These barriers affected the physicochemical behavior of the drug. For instance, mostly hydrophobic and high molecular weight drugs may become entrapped because when administered orally, they first contact the gastrointestinal (GI) mucus layer that limits their access to the epithelial surface. They next contact the intestinal epithelium, which, due to tight junctions, restricts paracellular transport of a poorly permeable compound.

P-glycoprotein acts as an efflux transporter that blocks or reduces intracellular drug accumulation. Enzymatic breakdown within the GI tract, along with pre-systemic hepatic metabolism, further decreases the fraction of drug reaching systemic circulation. Slight changes in gastrointestinal pH and transit time can easily affect the drug dissolution and stability, especially for pH-sensitive compounds.

Collectively, these barriers create the problem of poor bioavailability and emphasize the need for an advanced system that can overcome the challenges and facilitate alternative absorption pathways such as the lymphatic route.

2.5 Bioavailability

Beyond absorption: Bioavailability is not solely determined by the extent of absorption but is strongly influenced by pre-systemic metabolism, tissue distribution, and systemic clearance (Xie et al., 2024). Polymeric nanoparticles can increase bioavailability through the control of release kinetics, the increase in circulation time, and the decrease in the peak through variations (Akbarian and Chen, 2022). Delivery systems based on nanotechnology have statistically shown significant increases in bioavailability compared to traditional preparations, and the influence of nanoscale formulation design on systemic drug exposure has been highlighted. For example, encapsulation of biodegradable polymer nanoparticles can improve bio accessibility by ∼70%, showing that the pharmacokinetic effects of nanoscale carriers can be measured. PEG-functionalized nanocomposite materials exhibited a circulating half-life of up to 22 h compared to a half-life of 5 h recorded in the literature. Lipid nanoparticles (LNPs), especially after oral delivery, can increase bioavailability by enhancing lymphatics and thus avoiding hepatic first-pass metabolism.

In the case of parenteral delivery, the surface charge, the size of the nanoparticles, and surface science are of paramount importance for protein corona formation, biodistribution, and mononuclear phagocyte system clearance (Senthilraja, 2022). All these factors indicate that bioavailability is a system-level outcome of interaction between formulation properties and biological processes and not an individual parameter related to absorption.

2.6 Limitations of classical metrics in nanoparticle systems

Small-molecule formulations have established solubility and dissolution metrics, but they do not usually accurately predict the in vivo performance of systems based on nanoparticles (Sánchez et al., 2020). Dynamic physiological influences on in vitro release assays include shear stress, enzymatic activity, or nanoparticle interactions with proteins, which may not be included in in vitro release assays. As a result, low in vitro–in vivo correlation (IVIVC) can still be regarded as a significant issue of nanomedicine development.

To close the gap between formulation design and clinical performance, it is thus necessary to integrate the mechanistic understanding and predictive testing models. Table 1 compares the traditional understanding of solubility and stability with the latest understanding that can be applied to nanoscale preparations to explain the fundamental changes in classical pharmaceutical paradigms with nanoparticle-based DDSs (Stielow et al., 2023). This comparison explains the flaws of conventional metrics and warrants system-level evaluation strategies in the development of nanomedicine.

TABLE 1. Comparative highlights: Interpretation of key examination and approaches between traditional vs. nanoparticle-based drug delivery systems.

The collaborative role is discussed in the following sections on how these principles are implemented in both systems of nanoparticles.

3 Polymeric nanoparticles

Polymeric nanoparticles are one of the most studied and clinically developed nanocarrier systems for drug delivery. Biodegradable polymers such as polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA) (Cu and Saltzman, 2009), and polyethylene glycol (PEG)-based copolymers dominate clinically relevant designs due to their established safety results, adjustable physicochemical properties, and regulatory acceptance. These polymers allow the encapsulation of poorly aqueous soluble drugs in amorphous form or molecular dispersions, leading to significant increases in apparent solubility and dissolution rates (Sánchez-Félix et al., 2020). Nanoscale (<100 nm) improves expanse and increases the dissolution rate, contributing to improved bioavailability (Bhakay et al., 2018).

In addition to improving solubility, polymeric nanoparticles provide strict control of drug release kinetics. Labile molecules are shielded against chemical and enzymatic degradation, and surfaces can be reformulated to customize the pharmacokinetics and biodistribution. Depending on polymer composition and architecture, these systems can be optimized for sustained, targeted, or stimuli-responsive delivery (Karalis et al., 2008). Together, these properties make polymeric nanoparticles especially able to overcome formulation issues that are linked to hydrophobic drugs, macromolecules, and compounds with narrow therapeutic indices.

3.1 Different classes of polymeric nanoparticles

3.1.1 PLGA nanoparticles

PLGA nanoparticles are the most widely investigated and clinically used polymeric systems due to their biodegradability (Kim et al., 2025) and the ability to be used for parenteral and implantable compounds (Stevanović et al., 2025). The degradation rate is accurately controlled by changing the ratio of lactic to glycolic acid and molecular weight to allow controlled and prolonged drug delivery (Halwani, 2022). PLGA nanoparticles have also been shown to have excellent solubility (Jumadi et al., 2026) and pharmacokinetics improvements with various poorly soluble drugs (Gagliardi et al., 2021).

3.1.2 Polymeric micelles

These are the products of the self-assembly of amphiphilic block copolymers in aqueous solution (Singh et al., 2026). They are a core-shell structure that comprises a hydrophobic core on which poorly water-soluble drugs are solubilized and a hydrophilic corona that offers steric stability and extends the systemic circulation (Liu et al., 2024). These features render polymeric micelles a good choice for highly hydrophobic compounds with a low dose (Kamaly et al., 2016). These particles have been found to increase apparent solubility by one to two orders of magnitude and reduce aggregation and precipitation of drugs (Allahyari and Mohit, 2016).

3.1.3 Dendrimers

These are monodispersed, ramified polymers that contain a defined molecular structure and a wide number of surface functional groups. Structural accuracy enables a high drug-loading ability by encapsulation, electrostatic repulsions, or covalent conjugation (Pérez-Ferreiro et al., 2023). Moreover, dendrimers can undergo extensive targeting ligand or stimuli-responsive moiety functionalization to attain site-specific delivery. Despite these merits, clinical translation of dendrimer-based systems is still hindered by synthetic complexity, scale-up issues, and issues of long-term biocompatibility and toxicity. However, dendrimers are useful in exploring the study of precision drug delivery and multifunctional nanomedicine design (Chis et al., 2020).

3.1.4 Natural polymer nanoparticles

Nanoparticles that are derived from natural polymers, including chitosan, alginate, and gelatin, have biocompatibility and biodegradability. Basically, has received specific concern owing to its mucoadhesive quality, as well as its capacity to increase epithelial permeability (Geszke-Moritz and Moritz, 2024). These properties improved GI retention and absorption.

3.1.5 PEGylated and surface-engineered polymers

PEGylated surfaces are important in enhancing the in vivo behavior of polymeric nanoparticles (Suk et al., 2016). PEGylation has been extensively used to minimize opsonization and decrease mononuclear phagocytic system clearance. The conjugation of targeting ligands can be used to selectively deliver the ligand to tumors, inflamed tissues, or receptor-expressing cells. The latest advance is the utilization of stimuli-responsive polymeric systems that deliver drugs into the body according to pH, redox conditions, temperature, or enzymatic activity. Hybrid polymeric platforms that integrate multiple polymer/combine polymeric cores with lipid components have also emerged, offering synergistic improvements in stability, bioavailability, and cellular uptake.

3.2 Advanced research: absorption enhancers, mucoadhesion, and surface modification

In addition to simple encapsulation and release control, polymeric nanoparticles may be functionalized with additional characteristics to further improve the therapeutic outcomes. Mucoadhesive polymers such as chitosan can be used as an absorption enhancer to improve epithelial absorption of poorly absorbed drugs by increasing the residence time in the gastrointestinal tract. Surface modification of the particles can be used to deliver the encapsulated drug to targeted tissues or cells, which can be achieved by conjugating ligands to the surface of the particles. The use of stimuli-sensitive polymeric particles, which respond to various biological conditions such as pH, redox potential, enzymes, or temperature, allows the controlled release of the encapsulated drug.

4 Lipid-based nanoparticles (LNPs)

Lipid-based nanoparticles have emerged as a surface of present-day nanomedicine, providing biocompatibility, flexibility in delivery, and the capacity to absorb hydrophilic and hydrophobic compounds (Mehta et al., 2023). They increase the solubility, stability, and systemic bioavailability of drugs that are not soluble in aqueous solutions and stabilize labile macromolecules, including nucleic acids and proteins. LNPs are distributed in liposomes, solid (Singh and Kumar, 2025) lipid nanoparticles (SLNs), ionizable lipid nanoparticles, nanostructured lipid carriers (NLCs), and hybrid lipid–polymer systems, each offering unique physicochemical and pharmacokinetic advantages (Munot et al., 2022). Their clinical success, especially in vaccine technology, has enhanced global interest in the scientific platforms as versatile DDSs (Hsu et al., 2013).

4.1 Types of lipid-based nanoparticles

4.1.1 Solid lipid nanoparticles

SLNs are composed of lipids that are solid at room and body temperature, which are stabilized using surfactants. Some examples of SLNs include the formulation of ibuprofen by SLNs to increase its solubility and oral absorption. SLN formulations of vitamin A have an initial burst release and then a sustained release (Ladetto et al., 2025). Challenges with SLNs include low drug loading and drug expulsion during storage, caused by lipid recrystallization.

4.1.2 Nanostructured lipid carriers

These are second-generation technologies, consisting of solid lipids and liquid lipids. NLCs are delivered orally, topically, and intravenously (Jain et al., 2018) and improve the solubility of formulations (Shete et al., 2014).

4.1.3 Liposomes

Liposomes are vesicles, constructed of phospholipid bilayers, that enclose water-loving drugs as the principal and hydrophobic drugs as the 2-layer. Doxil® and AmBisome® are clinically approved liposomal preparations that enhance drug stability and reduce toxicity (Mukai et al., 2022; Creutzig et al., 2013). Liposomes have been shown to increase the stability of drugs and decrease drug toxicity, which is an important benefit of liposomes in mRNA COVID-19 vaccines (Negari et al., 2025; Song et al., 2006). They offer enzymatic breakdown, improved circulation time, and resistance to toxicity (Ukawala et al., 2012).

4.1.4 Lipid nanoparticles

LNPs are widely used for the delivery of nucleic acids. Their advantages include high encapsulation (Schober et al., 2024), prevention of enzymatic degradation, endosomal escape capabilities (Nourafkan et al., 2025), and high bioavailability by parenteral routes. Similarly, Amphotericin B liposomes (AmBisome 2000) are clinically approved. These clinically approved examples demonstrate that improvements in stability, biodistribution, and pharmacokinetics using lipid nanocarriers can lead to successful therapeutic products.

4.1.5 Hybrid lipid–polymer nanoparticles

Hybrid nanoparticles combine the stability of polymers with the biocompatibility of lipids (Jacob et al., 2025), which leads to enhanced loading and control of the drug (Tahir et al., 2019), targeted biodistribution (Joseph et al., 2022), greater solubility in the biological fluids (Wang et al., 2010), protection from enzymatic degradation (Wu et al., 2014; Jain et al., 2023), and LNP–polymer siRNA carriers that improve stability and intracellular release (Ahl, 2025).

4.2 Other strategies

The functional strategies can also be used to modify lipid-based nanoparticles to improve performance. PEGylation prolongs the circulation time and improves the coating, thereby reducing the rate of immune clearance. Additionally, the use of ligands enables the targeted delivery of the drug to the desired area of the body. Mucoadhesive lipid formulations increase gastrointestinal absorption and residence time, especially under oral delivery. Lipid nanoparticles can be designed to release the drug in the targeted cells after a change in the environment, such as the pH change in the vesicle after engulfing the nanoparticle, which enables the drug to be released into the targeted cells. These functional methods complement the solubility, stability, and bioavailability advantages of lipid nanoparticles and provide them with versatile platforms of improved drug delivery functions.

Polymer and lipid nanoparticles have complementary strengths that determine the platform to use in actual formulation development. Polymeric systems are better in terms of structural tunability, modulation of release, and targeting flexibility and are therefore applicable in the sustained delivery of small molecules and macromolecules with specific pharmacokinetic control needs. However, their production might entail complicated processing and solvent management factors. Conversely, lipid-based nanoparticles offer outstanding biological environments, lipophilic drug solubility, and well-established translational efficacy, specifically in nucleic acid therapeutic delivery. Loss of drugs, stability, and reduced ability to control the kinetics of release may be within their limitations compared with polymeric matrices. This means that to make a rational choice of platform, physicochemical drug characteristics, therapeutic aims, manufacturability, and regulatory practicability must be balanced instead of being based on the theoretical performance benefits.

To enable platform choice, Figure 1 presents a decision-tree framework for selecting nanoparticle delivery systems based on drug physicochemical properties and therapeutic requirements. The workflow begins by classifying the payload as nucleic-acid-based or small-molecule/peptide-based, followed by evaluation of oral bioavailability needs and lipophilicity. Each decision node represents a binary question guiding formulation selection. Lipid-based systems, including SLNs, liposomes, and NLCs, are considered where lymphatic uptake or high drug loading is required, while polymeric nanoparticles are suggested for sustained-release applications.

Table 2 describes the numerical data analysis with mechanistic behavior examples from published studies of both lipid-based and polymeric systems, which increase the solubility, achieving fold improvements compared to other formulations. Table 3 describe the various procedure method with their advantages and disadvantages.

TABLE 2. Comparative mechanism analysis of polymeric nanoparticles and lipid-based nanoparticles with examples.

TABLE 3. Types of methods used in nanoformulation with their advantage and disadvantages.

5 Why promising nanoparticle formulations fail in clinical translation

Although numerous nanoparticle-based DD systems have shown strong preclinical success, a range of formulation-related, biological, and translational issues has led to a lack of clinical approval, as shown in Figure 2.

5.1 Burst drug release

A common issue, particularly in polymeric and lipid-based nanoparticles with high surface-associated drug fractions, is rapid initial release (Yingchoncharoen et al., 2016). The burst effect may lead to transient toxicity, diminished sustained therapeutic exposure, and erratic in vivo performance (Bhattacharjee, 2021).

For example, the rapid release of paclitaxel from initial polymeric nanoparticle formulations led to dose-limiting toxicity, prompting reformulation efforts with multilayer-coated nanoparticles. Another example of a polymeric nanoparticle system has generally shown a high initial burst wherein approximately 10–80% of the drug entrained in the particles is released over the first day (Wang et al., 2002), after which a diffusion or degradation-controlled release is then observed. PLGA nanoparticle formulations have shown a cumulative release of approximately 44% in the first few hours in vitro (Yoo and Won, 2020), with 38%–47% release in the first few hours (Anwar Ul Alam et al., 2022). Different PLGA-based systems have reported different cumulative releases (Cetin et al., 2010).

5.2 Immune recognition and clearance

Nanoparticle surfaces can activate complement pathways or be opsonized by plasma proteins, leading to accelerated clearance by the mononuclear phagocyte pathway (Moghimi et al., 2023). Repeated administration of PEGylated liposome led to a systemic exposure reduction of approximately 50–80%, clearance increases of about 4-fold, and a half-life reduction in circulation of about 3–10-fold because of anti-PEG immune reactions (La-Beck et al., 2021). In other instances, the concentration of nanoparticles in the blood decreased nearly 90% in a few hours after the repeat doses, depicting the accelerated blood-clearance effect and rapid removal, which points to hidden challenges of current shielding methods (Chang et al., 2019).

5.3 Variability of batches

Consistency in manufacturing complex nanostructures is a major challenge, particularly when the desired product is a complex nanostructure that needs careful regulation of the particle size, drug loading, and surface chemistry (Bi et al., 2025). Any small deviation in scale-up can result in noteworthy changes in pharmacokinetics and medicinal outcomes and make regulatory approval and commercialization difficult (Nsairat et al., 2025).

Industrial issues are typified by scale-up failures in nanoprecipitation-based production that generated shifts in uneven particle sizes that are larger than the regulatory thresholds. Processing studies have revealed that the processing parameters can also vary the encapsulation efficiency or size distributions of particles significantly; for example, formulation parameters like sonication time can change the encapsulation efficiency from 78% to 97%, making formulation sensitive to process parameters.

5.4 Weak correlation between in vitro and in vivo

Simplified in vitro models of release have been shown to exhibit poor dynamic physiological correlations (Wang et al., 2025), such as enzyme degradation, shear stress, and protein corona formation (Ikegami, 2003). Consequently, in vitro projections of drug release and bioavailability are often not observed in vivo.

5.5 Translational mismatch between animals and humans

Metabolism, immune response, and pathophysiology of disease. The difference in the metabolism, immunity, and disease pathophysiology of animal models and humans can result in overestimated efficacy or underestimated toxicity in preclinical studies (Tsantili-Kakoulidou and Demopoulos, 2021). Such discrepancies highlight the need for more human-related predictive test models. The solution to these translational barriers is a change in strategy to one focused on rational design, predictive testing models, and scalable manufacturing strategies (Savla et al., 2017). It is on these grounds that the future directions of nanoparticle-based drug delivery can be discussed, which is the topic of the next section.

5.6 Manufacturing and regulatory issues

Manufacturing challenges were the major hurdle at the time of formulation. Many physicochemical parameters, experimental conditions, and batch variability affect product safety and efficacy. From a regulatory perspective, the lack of standardized evaluation frameworks for nanomedicines further complicates clinical translation. Additionally, regulatory agencies require extensive characterization and safety data, which can prolong development timelines and increase costs. Regulatory review of nanomedicines frequently requires advanced characterization, such as morphology imaging and stability mapping, increasing development costs.

The framework integrates therapeutic payload class (nucleic acid vs. small molecule/peptide), key physicochemical properties (e.g., lipophilicity and LogP), delivery objectives (oral bioavailability and sustained release), and translational constraints (manufacturing scalability and regulatory precedent) to guide rational nanoparticle platform selection. Ionizable lipid nanoparticles are prioritized. Nucleic acid delivery is preferred to ionizable lipid nanoparticles because of their pH-responsive endosomal escape, but polymeric and lipid-based nanoparticles are compared in terms of drug lipophilicity, dose needs, release kinetics, and scalability, as discussed below in Table 4, while the challenges, failures, reasons, and causes are discussed in Table 5.

TABLE 4. Decision-oriented selection guide for choosing a system.

TABLE 5. Challenges causing possible failure in the design of nanoparticle-based drug delivery systems.

6 Future perspectives

6.1 Converging future of nanoparticle drug delivery systems

Polymer- and lipid-based nanoparticles have been developed from proof-of-concept investigations to become commercially and clinically viable. Instead of merely highlighting the necessity of further research, now it is possible to predict what platforms will perform well in clinical translation, which may have its constraints, and how regulations will influence development. The most important aspects that affect these trends are scalability, manufacturability, regulatory precedents, and design approaches based on data (Chauhan and Malik, 2025).

6.2 Expansion of AI-guided and data-supported design of formulation

One of the most significant change processes in nanoparticle development is the adoption of artificial intelligence (AI) that gives successful results with machine learning (ML) in the formulation development process. The possibilities of AI-based platforms include the following:

• Minimizing trial-and-error in excipient and material selection.
• Reducing experimentation in the choice of excipients and materials.
• Anticipating the stability of nanoparticles, drug loading, and release.
• Predictive modeling with specific patient groups or disease signs.
• Predicting nanoparticle stability, drug loading, and release profiles.
• Optimizing formulations for specific patient populations or disease indications.

With the increase in the number of formulation datasets and the growing acceptance of model-driven strategies by regulatory authorities in the last 5 years, AI-aided design could become an instrument of research and a more regulatory-friendly strategy, especially in Quality by Design (QbD) frameworks.

7 Conclusion

Drug delivery systems using nanoparticles, especially polymer-based and lipid-based nanoparticles, have revolutionized the field of contemporary therapy. These platforms have evolved during the past 20 years, and now they are considered clinically viable technologies with the potential to increase drug solubility as well as stability and targeted delivery. The success in the delivery of small molecules, nucleic acids, and proteins by lipid-based nanoparticles, that is, liposomes, ionizable LNPs, or any other categories of nanoparticles, has been remarkable. Polymeric and hybrid lipid–polymer nanoparticles also increase the area of designs with more control over release, increased drug loading, and targeting. Although these achievements have been made, translation challenges remain. The factors of burst drug release, immune recognition, batch variability, lack of in vitro and human in vivo correlation, and animal–human translational mismatches are what make many promising formulations fail in clinical development. To solve these issues, rational design solutions, predictive testing models, scalable manufacturing, and solution-oriented approaches to the regulatory features are needed. In the future, nanoparticle formulation is set to transform with the introduction of AI and data-driven formulation. AI has the potential to decrease empirical experimentation, optimize stability and drug release profiles, and adjust the formulations to disease-specific scenarios or patient populations. These methods, together with decision-tree models and design-rule matrices, provide a road map to expedite the bench-to-bedside translation. The combination of advanced nanoparticle platforms, mechanistic design strategies, and computational tools represents a promising direction for the future generation of nanomedicines. These systems are optimally placed to provide better, safer, and more clinically relevant therapeutics addressing existing translational barriers through the application of cutting-edge technologies. Further interdisciplinary studies that cut across materials science, pharmacology, and computational modeling can achieve successful nanoparticle-enabled drug delivery.

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Footnotes

Edited by: Van-An Duong, University of Texas Health Science Center at Houston, United States

Reviewed by: Suren Azad Ramadhan, Knowledge University, Iraq

Hanaa Hussein, University of Basrah, Iraq

Footnotes

AI, artificial intelligence; DD, drug delivery; IVIVC, in vitro–in vivo correlation; LNPs, lipid nanoparticles; NLC, nano lipid carrier; NPs, nanoparticles; PEG, polyethylene glycol; SLNs, solid lipid nanoparticles.