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Frontiers in Biomaterials Science ·

Volume 5 - 2026 | https://doi.org/10.3389/fbiom.2026.1911811

Elastin-like polypeptides in radiopharmaceutical delivery: current evidence, design principles, and translational challenges

  • Haidong Tian1,2*corresponding author
  • Kepei Yang3
  • Hongyan Li2
  • Jianxi Xiao1*corresponding author
  1. 1State Key Laboratory of Nature Product Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu, China
  2. 2Department of Medical Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu, China
  3. 3Gansu TCM Modern Pharmacy Engineering Research Institution Co. Ltd., Lanzhou, Gansu, China
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Abstract

Elastin-like polypeptides (ELPs) are genetically engineered protein polymers with tunable sequences, molecular weights, phase-transition temperatures, and functional sites. Their programmable and thermoresponsive properties allow control over solubility, self-assembly, and local retention, supporting their use as carriers for radiopharmaceutical delivery. This review summarises ELP properties relevant to nuclear medicine and discusses radioiodination, radiometal chelation, site-specific conjugation, and self-assembly-based loading. It also examines three main delivery modes: systemic delivery, thermally triggered lesion enrichment, and local in situ depot formation. We discuss how molecular design, labelling chemistry, formulation, and the route of administration affect radiochemical stability, biodistribution, and dose deposition. Potential applications include tumour imaging, radionuclide therapy, and multimodal treatment. Important challenges include preserving ELP function after labelling, maintaining in vivo stability, and establishing scalable manufacturing and quality-control procedures. Biosafety, immunogenicity, repeat-dose effects, and regulatory requirements also require systematic evaluation. Continued optimisation may support the development of ELP-based systems for controlled radionuclide delivery and cancer theranostics.

Keywords

1 Introduction

Nuclear medicine is an important component of precision medicine. It uses radiopharmaceuticals to deliver radionuclides to diseased tissues or molecular targets for imaging, staging, targeted therapy, and treatment monitoring (Sgouros et al., 2020; Vermeulen et al., 2019). Advances in positron emission tomography (PET), single-photon emission computed tomography (SPECT), targeted radionuclide therapy (TRT), and theranostics have broadened this role. Radiopharmaceuticals now support disease detection, dosimetric assessment, precision treatment, and longitudinal monitoring within an integrated framework (Rudd, 2026; Hu et al., 2025).

The therapeutic effects of radiopharmaceuticals arise from ionising radiation emitted during radionuclide decay, including α-particles, β-particles, and Auger electrons (Liu et al., 2026; Silindir-Gunay et al., 2020). These emissions can cause single- and double-strand DNA breaks, cell-cycle arrest, oxidative stress, and cell death, thereby suppressing tumour growth (Ordas et al., 2026). Clinical performance depends on both radionuclide properties and carrier behaviour. Relevant radionuclide properties include physical half-life, radiation type, emission energy, and tissue range. The delivery system determines biodistribution, target accumulation, local retention, clearance, and dose deposition (Gebruers et al., 2025; Pandya et al., 2026). Effective treatment therefore requires alignment of physical half-life with biological kinetics and measurement of time-integrated activity in lesions and dose-limiting organs (Koo et al., 2026; Meng et al., 2026). Accordingly, rationally engineered delivery systems may improve radiopharmaceutical efficacy and safety and support broader clinical use (Shahiwala, 2026; Guo et al., 2026).

Radiopharmaceutical carriers include small molecules, functional peptides, antibodies and antibody fragments, nucleic acid aptamers, nanoparticles, and natural biopolymers (Kang, 2026; Luo et al., 2025; Mao et al., 2025; Tartis et al., 2008). Each class offers a different balance of tissue penetration, circulation, targeting, and clearance. Small molecules and short peptides usually penetrate tissues rapidly and provide favourable imaging kinetics, but rapid clearance can limit lesion retention and sustained dose deposition (Olberg and Hjelstuen, 2010; Tornesello et al., 2017). Antibodies provide high affinity and specificity, whereas their prolonged circulation may increase radiation exposure to the bone marrow, liver, and spleen. Nanoparticles offer high loading capacity and multifunctionality, but reticuloendothelial uptake, persistent tissue retention, manufacturing complexity, and batch variability can hinder translation (Fletcher et al., 2026; Sakr et al., 2018; Majima et al., 2025; Lee et al., 2025; Huang Y. et al., 2026; Tian et al., 2025). Table 1 compares these carriers with ELP-based systems.

TABLE 1. Comparison of radiopharmaceutical delivery carriers.

Carrier typeKey advantagesMajor limitationsComparison with ELP-based carriersReferences
Small-molecule carriersDefined structures, established synthesis, strong tissue penetration, and rapid imaging kineticsRapid clearance, limited lesion retention, and insufficient sustained dose depositionELPs may prolong local retention through molecular-weight control and thermoresponsive phase behaviourLuo et al. (2025), Olberg and Hjelstuen (2010)
Peptide carriersFlexible targeting design, small size, and favourable tissue penetrationEnzymatic degradation, short circulation, and potential renal uptakeELP sequence, molecular weight, and transition temperature can be adjusted to modify stability and pharmacokineticsTornesello et al. (2017), Fotou et al. (2026)
Antibodies and antibody fragmentsHigh binding affinity and target specificityIntact antibodies circulate slowly and may increase normal-tissue radiation exposureELPs can be engineered to balance lesion exposure, systemic clearance, and safetyKang (2026), Mao et al. (2025), Majima et al. (2025)
Nanoparticle carriersHigh loading capacity and multifunctional integrationReticuloendothelial uptake, persistent retention, complex production, and batch variabilityELPs are biodegradable and genetically programmable, which may support more defined productionSilindir-Gunay et al. (2020), Fletcher et al. (2026), Sakr et al. (2018), Lee et al. (2025), Tian et al. (2025)
ELP-based carriersProgrammable, thermoresponsive, and self-assembling; suitable for systemic, thermally triggered, or local deliveryIn vivo phase behaviour, long-term safety, and translational standards require further validationELPs are adaptable carriers whose value must be demonstrated for each radiolabelled productGuo et al. (2023), Van Strien et al. (2023), Varanko et al. (2020)

Elastin-like polypeptides are genetically engineered biomimetic polymers derived from conserved motifs in natural elastin (Guo et al., 2023; Varanko et al., 2020; Riziotis et al., 2021). Their chain length, labelling sites, and phase-transition temperature can be encoded genetically or adjusted chemically. Most ELPs contain repeats of the pentapeptide VPGXG, in which the guest residue X and repeat number influence hydration and lower-critical-solution-temperature behaviour. Selected constructs remain soluble below their transition temperature and form coacervates, micelles, or crosslinked depots above it. These features provide three functions relevant to nuclear medicine: a defined scaffold for radiolabelling, an imageable macromolecule for pharmacokinetic studies, and an injectable material for local radionuclide retention (Van Strien et al., 2023; Gupta et al., 2026; Janib et al., 2013; Liu et al., 2010).

These properties make ELPs suitable candidates for radiopharmaceutical delivery. Amino acid composition, repeat number, molecular weight, phase-transition temperature, and functional sites can be adjusted to influence pharmacokinetics, target accumulation, local retention, and dose deposition (Huang et al., 2025; Tofik et al., 2026; Sarangthem et al., 2020; Nazari and Rabiee, 2026). This review summarises the structural and thermoresponsive features of ELPs that are relevant to radionuclide delivery. It then discusses radiolabelling strategies, delivery modes, application scenarios, design parameters, and translational challenges. Finally, it outlines priorities for the further development of ELP-based systems in cancer imaging and therapy.

2 Radiopharmaceutically relevant properties of ELPs

2.1 Sequence, phase behaviour, and functional handles

The transition temperature of an ELP is not a fixed material constant. It depends on guest-residue composition, molecular mass, polymer concentration, ionic strength, co-solutes, attached cargo, and the heating or cooling protocol (Tanaka et al., 2026; Asaei et al., 2026; Qiu et al., 2023; Chakravarti and Joseph, 2025; Mukherjee et al., 2025). Hydrophobic substitutions and higher concentrations often lower the transition temperature, although the extent is construct-specific. The transition profile should therefore be measured for the final labelled product at the administered concentration and in the intended vehicle. Measurements of an unlabelled precursor do not show whether the radioconjugate will remain injectable or form a depot at 37 °C (Asaei et al., 2026; Chakravarti and Joseph, 2025; Zhao et al., 2026). Hydrophilic or charged residues can increase hydration, transition temperature, solubility, and colloidal stability under physiological conditions (Nazari and Rabiee, 2026; Qiu et al., 2023; Phan and MacKay, 2024). Genetic design can also position tyrosine, cysteine, lysine, or unique terminal groups outside the repetitive domain. A C-terminal tyrosine tract was used in extensively studied iodine-125/iodine-131 depots, whereas an N-terminal sarcophagine derivative enabled site-specific copper-64 labelling (Janib et al., 2013; Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016). Defined placement improves control over labelling stoichiometry and allows direct testing of changes in transition temperature, oligomerisation, serum stability, or binding activity (Choi et al., 2014; Jiang et al., 2026; Sugiura et al., 2014). Figure 1 summarises how these design features support thermally responsive radionuclide delivery.

Schematic overview of ELP-based radiopharmaceutical delivery platforms. ELPs contain repetitive VPGXG motifs and can be engineered by varying the guest residue, repeat number, molecular weight, transition temperature, and functional sites. Radioiodination, radiometal chelation, site-specific labelling, and self-assembly-based loading may be used to regulate radionuclide accumulation, local retention, release, dose deposition, and off-target exposure.
Figure 1. Schematic overview of ELP-based radiopharmaceutical delivery platforms. ELPs contain repetitive VPGXG motifs and can be engineered by varying the guest residue, repeat number, molecular weight, transition temperature, and functional sites. Radioiodination, radiometal chelation, site-specific labelling, and self-assembly-based loading may be used to regulate radionuclide accumulation, local retention, release, dose deposition, and off-target exposure.

2.2 Self-assembly and loading capacity of ELPs

ELPs offer precise control over sequence, repeat number, molecular weight, and functional sites through recombinant production (Guo et al., 2023; Varanko et al., 2020; Riziotis et al., 2021; Roland et al., 2023). Molecular size influences clearance, organ deposition, and the time available for tumour uptake. Fluorescence studies of 25–110 kDa ELPs reported longer terminal plasma half-lives with increasing size and substantial size-dependent renal deposition (Sarangthem et al., 2020). Studies of multivalent and self-assembled architectures further indicate that molecular mass, conformation, and steric stabilisation affect organ distribution and colloidal behaviour (Tofik et al., 2026; Lin and Baneyx, 2026; Li et al., 2023; Browning et al., 2026). These non-radioactive findings are indirect. They identify size as an important variable but cannot define an optimal radiopharmaceutical size, because longer residence also changes integrated exposure in blood, kidney, liver, and marrow (Van Strien et al., 2023; Huang et al., 2025; Nazari and Rabiee, 2026; Zhao et al., 2026).

ELPs can also be functionalised through genetic fusion or site-specific chemical modification. Targeting groups such as RGD peptides, prostate-specific membrane antigen ligands, fibroblast activation protein-targeting peptides, antibodies, and antibody fragments may improve recognition of selected tissues or cell populations (Goel et al., 2026; Gong et al., 2025; Moktan and Raucher, 2012; Yuan et al., 2026; Ramamurthi et al., 2021; Li et al., 2024). Tyrosine, cysteine, lysine, and noncanonical amino acids can provide defined sites for radiolabelling or chelator attachment. Bifunctional chelators such as DOTA, NOTA, and DTPA can coordinate radiometals and may improve complex stability and in vivo retention (Cai and Anderson, 2014; Valkenburgh et al., 2026; Jain et al., 2018; Jozi et al., 2026; Machulkin et al., 2026; Shetty et al., 2026). These modular approaches can combine targeting, radionuclide attachment, payload delivery, and stimulus responsiveness within one construct (Zhou et al., 2026; Pozdniakova et al., 2022; Guo et al., 2025).

Amphiphilic ELP block copolymers can self-assemble into micelles, vesicles, nanoparticles, and related nanostructures under suitable conditions (Van Strien et al., 2023; Li et al., 2023; Browning et al., 2026; Kim et al., 2026). Hydrophobic domains can accommodate hydrophobic drugs, radiolabelled compounds, or other agents, whereas the hydrophilic corona supports aqueous dispersibility and colloidal stability (Tofik et al., 2026; Phan and MacKay, 2024; Trusso et al., 2026; Daniel et al., 2026; Huang H. et al., 2026; Yao and Xiao, 2026). Compared with conventional nanocarriers, ELP assemblies may offer greater sequence definition and compositional control. However, these advantages must be demonstrated for the final radiolabelled formulation rather than inferred from the unlabelled material.

Systemically administered macromolecules are also affected by the heterogeneous enhanced permeability and retention (EPR) effect. Vascular density, perfusion, pore structure, interstitial pressure, extracellular matrix, lesion size, and previous treatment vary within and between tumours. Human lesions are generally more heterogeneous than rapidly growing xenografts, and average nanoparticle delivery remains low. For ELP radiopharmaceuticals, EPR should therefore be treated as a patient- and lesion-specific factor. Dynamic imaging and lesion-level time-activity curves are more informative than a general claim of passive targeting.

2.3 Biocompatibility of ELPs

ELPs are derived from conserved motifs in natural elastin and have shown favourable biocompatibility and potential biodegradability (Guo et al., 2023; Varanko et al., 2020; Daniel et al., 2026; Ryu and Raucher, 2015). Unlike nondegradable inorganic materials and some synthetic polymers, ELPs are protein-based and can enter normal metabolic pathways (Varanko et al., 2020; Wirtz et al., 2024). Endogenous proteases may gradually degrade ELP chains into smaller peptides and amino acids that are subsequently eliminated (Varanko et al., 2020; Ryu and Raucher, 2015). This behaviour may reduce risks associated with persistent tissue accumulation, chronic inflammation, and delayed toxicity, although safety must be established for each final formulation.

Genetic engineering also enables the production of ELPs with predetermined sequences and relatively uniform molecular structures. This may reduce broad molecular-weight distributions, batch variability, and residual synthetic impurities associated with some conventional polymers (Guo et al., 2023; Varanko et al., 2020; Riziotis et al., 2021; Roland et al., 2023; Chu et al., 2010). Greater molecular definition can support reproducibility, quality control, safety assessment, and clinical translation (Sugiura et al., 2014; Ko et al., 2026). For radiopharmaceutical use, however, the critical product is the radiolabelled ELP rather than the recombinant precursor alone. Sequence identity, molecular-mass distribution, soluble aggregates, transition temperature, reversibility, and endotoxin burden should be assessed together with radiochemical identity, yield, purity, molar or mass activity, and formulation and serum stability. Radiolysis may cause oxidation, fragmentation, or crosslinking that is absent from the non-radioactive precursor. These changes can alter phase behaviour and biological clearance.

Together, these properties provide a programmable and thermoresponsive biomaterial platform. Appropriate molecular design may help control radionuclide distribution and local retention while limiting exposure to healthy tissues. The extent of any benefit, however, must be determined for each radiolabelled construct under relevant biological conditions.

3 ELP radionuclide labelling technologies and delivery systems

3.1 Radionuclide labelling strategies

The choice of radiolabelling strategy depends on the radionuclide, diagnostic or therapeutic purpose, administration route, and ELP structure (Vermeulen et al., 2019; Sugiura et al., 2014; Ko et al., 2026). The main approaches are direct radioiodination, chelator-mediated radiometal labelling, site-specific conjugation, and self-assembly-based loading. They differ in labelling efficiency, radiochemical stability, pharmacokinetics, and quality-control requirements (Choi et al., 2014; Cai and Anderson, 2014; Valkenburgh et al., 2026; Ko et al., 2026). The method should therefore be selected for the intended formulation and use.

Direct radioiodination is a relatively simple and widely used labelling method (Vermeulen et al., 2019; Choi et al., 2014; Sugiura et al., 2014). Tyrosine residues in the ELP sequence allow radioiodine isotopes, including 123I, 124I, 125I, and 131I, to be introduced by electrophilic substitution on the aromatic ring (Choi et al., 2014; Fayez et al., 2024). This approach avoids an additional chelator and may preserve the ELP architecture, phase transition, and self-assembly. It has therefore been used for local injectable depots and short-term in vivo tracking (Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Meyer et al., 2001; Liu et al., 2006). In an early direct study, radioiodinated ELPs were used to test whether mild local hyperthermia increased tumour accumulation after intravenous administration. One hour of heating produced approximately twofold greater accumulation in SKOV-3 and D-54MG xenografts, with higher uptake than a soluble control. In that experiment, the radionuclides acted as paired tracers. Radioiodinated ELPs may nevertheless undergo in vivo deiodination, leading to activity in iodine-avid tissues such as the thyroid and stomach (Liu et al., 2010; Choi et al., 2014). High labelling density may also alter hydrophobicity, conformation, transition temperature, and biodistribution. Labelling site, density, radiochemical purity, and in vivo stability should therefore be optimised together (Choi et al., 2014; Sugiura et al., 2014).

Chelator-mediated labelling is commonly used for radiometals such as 68Ga, 64Cu, 111In, 177Lu, 90Y, and 225Ac. Bifunctional chelators, including DOTA, NOTA, and DTPA, can be attached to ELPs to coordinate radiometal ions (Cai and Anderson, 2014; Valkenburgh et al., 2026; Jozi et al., 2026; Machulkin et al., 2026; Shetty et al., 2026; Baier et al., 2026). Copper-64 PET has been used to compare ELPs of different molecular sizes with a micellar assembly labelled through an N-terminal AmBaSar chelator. Serial imaging showed that architecture altered blood and organ kinetics, but the study did not identify a construct with superior tumour uptake or assess therapy. It is therefore best interpreted as a quantitative screening study rather than proof of systemic ELP tumour targeting. Stable chelation can reduce radionuclide dissociation, but performance depends on the metal-chelator pair, conjugation chemistry, labelling conditions, and in vivo stability. These variables must be optimised without disrupting ELP phase behaviour or pharmacokinetics (Janib et al., 2013; Jiang et al., 2026; Shetty et al., 2026).

Site-specific labelling can improve the homogeneity, reproducibility, and control of ELP radiopharmaceuticals (Choi et al., 2014; Jiang et al., 2026; Sugiura et al., 2014). Defined sites may be introduced by incorporating cysteine, lysine, tyrosine, or noncanonical amino acids into the sequence (Varanko et al., 2020; Pozdniakova et al., 2022). Bioorthogonal click chemistry, maleimide-thiol coupling, activated ester reactions, or enzymatic ligation can then attach radionuclides, chelators, or other functional groups. Compared with random modification, site-specific labelling provides better control over conjugation site and stoichiometry and may preserve ELP structure and function (Sugiura et al., 2014; Ko et al., 2026). It may also improve product uniformity, batch consistency, and dose reproducibility, which are important for manufacturing and clinical translation.

Beyond covalent conjugation, ELP self-assembly may provide a non-covalent route for loading radioactive cargo into micelles, nanoparticles, vesicles, or gel-like depots. Depending on the formulation, these structures could contain radiolabelled small molecules, radiometal complexes, or co-therapeutic agents within hydrophobic domains or aqueous compartments. The hydrophilic ELP corona may improve dispersibility and colloidal stability, but these properties must be confirmed in the final radiopharmaceutical. This modularity could support combined imaging and therapy with drugs, photothermal or photodynamic agents, or targeting ligands. However, direct radiopharmaceutical evidence for physically loaded ELP assemblies remains limited (Tian et al., 2025; Van Strien et al., 2023; Phan and MacKay, 2024; Daniel et al., 2026; Huang H. et al., 2026; Pyzhov et al., 2026; Yu et al., 2026). Important uncertainties include serum-induced rearrangement, premature release, dilution-driven disassembly, altered pharmacokinetics, and nonspecific uptake. Evaluation should therefore include cargo retention, assembly stability, release kinetics, biodistribution, and absorbed dose under physiologically relevant conditions. Overall, each labelling or loading strategy has distinct advantages and limitations. Further work should improve stability while preserving ELP structure, phase behaviour, and product reproducibility.

3.2 Primary delivery modes of ELP-Based radiopharmaceuticals

ELP radiopharmaceuticals can be grouped into three delivery modes: long-circulating systemic delivery, thermally triggered lesion enrichment, and local in situ depot delivery (Van Strien et al., 2023; Gupta et al., 2026; Ryu and Raucher, 2015). As shown in Figure 2, these modes differ in administration route, spatial control, and the strength of evidence supporting therapeutic use (Janib et al., 2013; Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Kelly et al., 2022; Schaal et al., 2022). Direct therapeutic evidence is strongest for locally injected radiolabelled depots, whereas systemic and thermally triggered approaches are supported mainly by radiotracer studies. Meaningful comparison should therefore consider lesion-to-organ activity ratios, spatial coverage, procedural feasibility, and product reproducibility.

Representative delivery modes for ELP-based radiopharmaceuticals. The three main modes are long-circulating systemic delivery, thermally triggered lesion enrichment, and local *in situ* depot therapy. They provide different degrees of systemic access, external spatial control, local radionuclide retention, and dose confinement.
Figure 2. Representative delivery modes for ELP-based radiopharmaceuticals. The three main modes are long-circulating systemic delivery, thermally triggered lesion enrichment, and local in situ depot therapy. They provide different degrees of systemic access, external spatial control, local radionuclide retention, and dose confinement.

Systemic delivery uses soluble ELP chains, macromolecular conjugates, or defined nanostructures. Molecular weight, conformation, surface charge, and hydrophilic-hydrophobic balance influence renal clearance, circulation, and organ uptake (Janib et al., 2013; Huang et al., 2025; Tofik et al., 2026; Sarangthem et al., 2020; Liu et al., 2006). Prolonged circulation is useful only if it improves lesion-to-blood and lesion-to-critical-organ time-integrated activity ratios (Pandya et al., 2026; Koo et al., 2026; Meng et al., 2026). A longer physical half-life may allow more time for tissue distribution, but slow clearance can also increase blood, liver, kidney, or marrow exposure (Koo et al., 2026; Liu et al., 2006; Croteau et al., 2026). Current evidence supports pharmacokinetic imaging and construct screening, but not yet systemic ELP-mediated radionuclide therapy.

Thermally triggered delivery uses the lower critical solution temperature (LCST)-type transition of ELPs (Tanaka et al., 2026; Asaei et al., 2026; Chakravarti and Joseph, 2025; Mukherjee et al., 2025). Suitable constructs remain soluble in circulation and undergo local phase transition when a lesion is exposed to clinically achievable mild hyperthermia (Moktan and Raucher, 2012; Ryu and Raucher, 2015; Meyer et al., 2001; Liu et al., 2006). Radiotracer studies reported greater ELP accumulation in heated tumours (Nazari and Rabiee, 2026; Ryu and Raucher, 2015; Meyer et al., 2001; Liu et al., 2006). However, increased uptake alone does not establish a higher absorbed dose or therapeutic benefit. Controlled studies should compare responsive and non-responsive ELPs in heated and unheated lesions using the same radiolabel. Serial imaging, intratumoural temperature mapping, and lesion-level dose assessment are also needed. Practical limitations include uneven heating, perfusion dependence, heat-induced vascular changes, and poor access to necrotic or weakly perfused regions.

Local in situ depots aim to retain radionuclides within accessible lesions and currently provide the strongest direct therapeutic evidence (Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Kelly et al., 2022; Schaal et al., 2022). After intratumoural or image-guided administration, selected ELPs can undergo phase separation, self-assembly, or gelation to form a radioactive depot (Zhao et al., 2026; Schaal et al., 2016; Liu et al., 2012; Pyzhov et al., 2026; Shamji et al., 2008). Preclinical radiolabelled depots have delayed tumour growth, although efficacy varied between models and complete spatial dose information was generally unavailable (Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Kelly et al., 2022; Schaal et al., 2022). Key practical considerations include injection geometry, multisite coverage, needle-track leakage, local normal-tissue exposure, and three-dimensional activity distribution. Systemic delivery provides whole-body access but is constrained by variable tumour delivery and organ exposure (Pandya et al., 2026; Tian et al., 2025). Thermal targeting adds external spatial control but requires reproducible heating (Ryu and Raucher, 2015; Meyer et al., 2001; Liu et al., 2006), whereas local depots improve retention but require accessible or image-guided lesions (Vermeulen et al., 2019; Koo et al., 2026; Ko et al., 2026). Selection should reflect radionuclide properties, ELP kinetics, lesion accessibility, activity ratios, and manufacturability.

4 Application scenarios and design strategies

4.1 Application scenarios

Among the proposed applications of ELP radiopharmaceuticals, local depot delivery has the clearest therapeutic rationale and the strongest direct preclinical support. In locally confined disease, systemic administration may provide insufficient lesion exposure while increasing normal-tissue exposure, although this balance must be measured for each construct (Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Kelly et al., 2022; Schaal et al., 2022). Conventional brachytherapy can deliver a high local dose, but implantation, irregular lesion geometry, and uneven source placement may complicate treatment (Schaal et al., 2016; Liu et al., 2012; Zhang and Liu, 2026). Injectable ELP depots may therefore complement, rather than replace, established brachytherapy when the lesion is accessible and spatial coverage can be confirmed.

Thermoresponsive ELPs can be formulated as injectable in situ radiopharmaceutical depots (Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Kelly et al., 2022; Schaal et al., 2022). Transition temperature, molecular weight, concentration, and radiolabelling chemistry jointly determine injectability, depot formation, and radionuclide retention. Formulations may be administered intratumourally or into a surgical bed under image guidance (Gebruers et al., 2025; Schaal et al., 2016; Liu et al., 2012). Phase separation, self-assembly, or gelation can then increase local residence and reduce early systemic redistribution (Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Kelly et al., 2022; Shamji et al., 2008). Bulk retention alone, however, does not show whether activity is distributed uniformly through the treated volume. Evaluation should include three-dimensional activity distribution, needle-track leakage, normal-tissue exposure, and temporal stability. Clinical suitability also depends on lesion accessibility, geometry, perfusion, and achievable injection coverage (Gebruers et al., 2025; Schaal et al., 2016; Liu et al., 2012).

ELPs may also be used as radiolabelled imaging carriers. Radionuclides considered for PET or SPECT include 68Ga, 64Cu, 124I, and 123I (Olberg and Hjelstuen, 2010; Janib et al., 2013; Cai and Anderson, 2014; Valkenburgh et al., 2026; Jain et al., 2018; Han et al., 2026; Yasin et al., 2026; Syed et al., 2022; Kim et al., 2017). The performance of an imaging construct depends on radiochemical purity, serum stability, target-to-background kinetics, and label-specific failure mechanisms. Serial quantitative imaging can measure blood clearance, organ uptake, lesion retention, and time-activity curves. These measurements may support construct selection, treatment planning, and patient stratification, although clinical utility remains unproven (Koo et al., 2026; Tartis et al., 2008; Fotou et al., 2026; Janib et al., 2013; Croteau et al., 2026; Syed et al., 2022; Kim et al., 2017; Sanad et al., 2026; Chen et al., 2026; Kown et al., 2002; Perkins and Frier, 2004). Imaging and therapy should be integrated only when the diagnostic label reliably predicts the distribution of the therapeutic construct.

Multimodal ELP systems could combine radionuclides with drugs, radiosensitisers, immunomodulators, photothermal agents, or targeting ligands (Mukerji et al., 2016; Goel et al., 2026; Moktan and Raucher, 2012; Ramamurthi et al., 2021; Li et al., 2024; Pozdniakova et al., 2022; Guo et al., 2025; Ryu and Raucher, 2015; Kelly et al., 2022; Schaal et al., 2022; Amarasekara et al., 2024; Cheng et al., 2026). Much of the supporting evidence, however, comes from non-radioactive ELP formulations or separate treatment modalities. It should be treated as indirect evidence rather than validation of a combined radiopharmaceutical. Hyperthermia may trigger ELP accumulation and modify radiation response, providing a rationale for combination treatment (Pandya et al., 2026; Van Strien et al., 2023; Varanko et al., 2020; Wang et al., 2026). Nevertheless, co-loading alone does not establish synergy. Components may differ in release, pharmacokinetics, dose-response relationships, and optimal timing (Moktan and Raucher, 2012; Ryu and Raucher, 2015; Meyer et al., 2001; Liu et al., 2006; Sun et al., 2023). Poor coordination may reduce efficacy or increase normal-tissue toxicity (Pandya et al., 2026; Wang et al., 2026; Van Damme et al., 2026). Factorial controls are therefore needed to distinguish additive from synergistic effects and to optimise cargo ratio, release, scheduling, dosimetry, and safety (Mukerji et al., 2016; Li et al., 2024; Kelly et al., 2022; Schaal et al., 2022).

Overall, current evidence most strongly supports ELPs as local depots and quantitative imaging tools. Systemic theranostics and multimodal combinations remain less mature. Further development should focus on reproducible radiochemistry, retained phase behaviour, measurable biodistribution, local leakage, and safety. These criteria can help identify constructs that justify further preclinical or clinical development.

4.2 Key design parameters and optimisation principles

The performance of an ELP radiopharmaceutical depends on the coordinated selection of sequence, phase-transition behaviour, radionuclide, radiolabelling method, administration route, and dosimetric characteristics (Vermeulen et al., 2019; Tian et al., 2025; Van Strien et al., 2023; Janib et al., 2013; Liu et al., 2010; Tanaka et al., 2026; Zhao et al., 2026; Schaal et al., 2016; Liu et al., 2012; Sugiura et al., 2014; Roland et al., 2023; Jain et al., 2018; Shamji et al., 2008; Shalgunov et al., 2022; Kim et al., 2017; Yang et al., 2025). Systemic formulations require sufficient circulation and lesion accumulation together with clearance from non-target tissues. Thermoresponsive systems also require alignment between the ELP transition temperature and the applied thermal stimulus (Tanaka et al., 2026; Chakravarti and Joseph, 2025; Mukherjee et al., 2025; Zhao et al., 2026; Li et al., 2023; Ryu and Raucher, 2015). Local in situ depots instead require rapid formation and prolonged retention at the administration site (Liu et al., 2010; Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Kelly et al., 2022). Design should therefore balance several parameters for a defined diagnostic or therapeutic purpose rather than maximise one property in isolation. Table 2 summarises the principal parameters and practical optimisation strategies.

TABLE 2. Key design parameters and optimisation strategies for ELP-based radiopharmaceutical delivery.

Design parameterMajor impactOptimisation strategyReferences
Guest residue at the X positionControls hydrophobicity, charge distribution, and transition temperatureAdjust the hydrophilic-hydrophobic balance for the administration route and target TtTanaka et al. (2026), Qiu et al. (2023), Pozdniakova et al. (2022)
Repeat number and molecular weightInfluences circulation, tissue penetration, lesion retention, and clearanceBalance tissue penetration and local retention against systemic exposureJanib et al. (2013), Sarangthem et al. (2020), Liu et al. (2006)
Transition temperature (Tt)Controls in vivo phase transition, self-assembly, or gelationSet Tt above body temperature for intravenous use, within the mild-hyperthermia range for thermal targeting, or near tissue temperature for local depot formationTanaka et al. (2026), Chakravarti and Joseph (2025), Mukherjee et al. (2025)
Radionuclide typeDefines imaging or therapeutic use, physical half-life, and radiation rangeMatch radionuclide properties to ELP kinetics and the intended applicationJanib et al. (2013), Choi et al. (2014), Sugiura et al. (2014), Cai and Anderson (2014), Valkenburgh et al. (2026)
Labelling strategyAffects radiochemical stability, product homogeneity, and in vivo dissociationUse a stable chelator and site-specific labelling when appropriateGoel et al. (2026), Gong et al. (2025), Yuan et al. (2026), Li et al. (2024), Jain et al. (2018), Pozdniakova et al. (2022)
Targeting ligand modificationInfluences lesion recognition and off-target uptakeOptimise conjugation site and ligand density without disrupting ELP phase behaviourGebruers et al. (2025), Liu et al. (2010), Schaal et al. (2016), Liu et al. (2012), Kelly et al. (2022)
Route of administrationDetermines initial distribution, access to the target, and clearanceUse intravenous administration for systemic or thermally triggered delivery and local injection for depot therapyLee et al. (2025), Janib et al. (2013), Tofik et al. (2026), Phan and MacKay (2024), Lin and Baneyx (2026), Li et al. (2023)
Assembly sizeInfluences tumour penetration, organ distribution, and dose depositionSelect size for the tumour, radiation range, and administration routeKoo et al. (2026), Meng et al. (2026), Croteau et al. (2026), Perkins and Frier (2004)
Dosimetric evaluationSupports absorbed-dose estimation, efficacy assessment, and normal-tissue safetyCombine PET or SPECT with dosimetric modelling to assess dose-response relationshipsKoo et al. (2026), Meng et al. (2026), Mukerji et al. (2016), Croteau et al. (2026), Perkins and Frier (2004)

The guest residue at the X position and the number of VPGXG repeats are primary sequence variables controlling ELP phase behaviour (Qiu et al., 2023; Pozdniakova et al., 2022). Guest-residue hydrophobicity, charge, side-chain structure, and conformational preference influence intermolecular interactions and the transition temperature (Tt) (Tanaka et al., 2026; Qiu et al., 2023; Chakravarti and Joseph, 2025; Mukherjee et al., 2025) These variables should be selected for the intended administration route. Intravenous formulations generally require a Tt above physiological temperature to limit premature aggregation (Riziotis et al., 2021; Nazari and Rabiee, 2026; Ryu and Raucher, 2015). Thermally targeted constructs require a Tt between body temperature and the applied mild-hyperthermia range (Moktan and Raucher, 2012; Ryu and Raucher, 2015; Meyer et al., 2001; Liu et al., 2006). Depot-forming constructs may use greater hydrophobicity or longer chains to promote local phase separation and retention (Liu et al., 2010; Zhao et al., 2026; Schaal et al., 2016; Liu et al., 2012; Pyzhov et al., 2026). Because Tt also depends on concentration and formulation, it should be measured in the final radiopharmaceutical under relevant conditions.

Chain length and molecular weight influence clearance, tissue penetration, and organ distribution, but the relationship is not monotonic. Lower-molecular-weight constructs often clear faster and may provide quicker background reduction for imaging (Janib et al., 2013; Sarangthem et al., 2020; Lin and Baneyx, 2026; Liu et al., 2006). Their shorter lesion residence may nevertheless limit time-integrated activity for therapy. Higher-molecular-weight constructs can prolong circulation and lesion exposure (Janib et al., 2013; Sarangthem et al., 2020; Liu et al., 2006), but may reduce tissue penetration or increase liver and spleen uptake. Molecular weight should therefore be selected from serial biodistribution and lesion-to-blood and lesion-to-organ activity ratios, rather than from circulation half-life alone.

Phase-transition behaviour and assembly size should be evaluated together because both may change after dilution, heating, or serum exposure (Van Strien et al., 2023; Tofik et al., 2026; Chakravarti and Joseph, 2025; Mukherjee et al., 2025; Phan and MacKay, 2024; Li et al., 2023). For intravenous use, the measured Tt should remain above physiological temperature (Nazari and Rabiee, 2026; Tanaka et al., 2026). For local depots, the formulation should support phase separation near tissue temperature without blocking injection or causing uncontrolled spread (Liu et al., 2010; Zhao et al., 2026; Schaal et al., 2016; Liu et al., 2012; Pyzhov et al., 2026; Shamji et al., 2008). Assembly size should reflect the administration route, vascular permeability, interstitial pressure, lesion geometry, and radionuclide emission range (Silindir-Gunay et al., 2020; Koo et al., 2026; Lee et al., 2025; Tian et al., 2025; Shalgunov et al., 2022). Small assemblies may clear or diffuse rapidly, whereas large assemblies may impair penetration and increase nonspecific organ uptake. These relationships should be measured in the final radiolabelled product.

Radionuclide selection should reflect ELP residence time and the spatial scale of the target. Decay before adequate lesion accumulation reduces usable signal or absorbed dose (Sgouros et al., 2020; Vermeulen et al., 2019; Koo et al., 2026; Zhang and Liu, 2026; Yang et al., 2025). Conversely, a long-lived radionuclide combined with slow clearance may increase blood and normal-organ exposure. Diagnostic labels should permit imaging at favourable target-to-background contrast, whereas therapeutic labels require sufficient lesion residence and in vivo stability (Ordas et al., 2026; Tornesello et al., 2017; Fotou et al., 2026; Sugiura et al., 2014). Emission range should also suit lesion size and activity distribution. Alpha-particle and Auger-electron emitters may be appropriate for small or microscopic deposits, but their short range makes heterogeneous delivery important (Silindir-Gunay et al., 2020; Baier et al., 2026; Shalgunov et al., 2022; Zhang and Liu, 2026). Beta emitters provide cross-fire across larger lesions but may extend dose beyond the target. For radionuclides with radioactive daughters, recoil-related redistribution should be assessed separately from parent retention.

Radiolabelling chemistry should retain the radionuclide without materially changing ELP behaviour (Vermeulen et al., 2019; Tian et al., 2025; Sugiura et al., 2014; Ko et al., 2026). For radioiodinated constructs, label stability and uptake in iodine-avid tissues, including the thyroid and stomach, should be measured. Tyrosine position and labelling density should be treated as formulation variables. For radiometals, DOTA, NOTA, or DTPA should be selected according to metal coordination chemistry and the required labelling conditions (Sakr et al., 2018; Jiang et al., 2026; Cai and Anderson, 2014; Valkenburgh et al., 2026; Jain et al., 2018; Jozi et al., 2026; Machulkin et al., 2026; Shetty et al., 2026; Baier et al., 2026). The effects of chelator attachment and labelling temperature on Tt, self-assembly, and pharmacokinetics should be tested (Janib et al., 2013; Kim et al., 2017). Physically loaded assemblies require separate measurements of cargo retention, serum stability, dilution-driven disassembly, and radionuclide release (Van Strien et al., 2023; Zhao et al., 2026; Phan and MacKay, 2024; Daniel et al., 2026; Huang H. et al., 2026; Yao and Xiao, 2026; Pyzhov et al., 2026; Yu et al., 2026). Because direct evidence for these systems is limited, loading capacity should not be used as a substitute for in vivo stability.

Targeting ligands may improve lesion uptake only if receptor binding compensates for changes in size, charge, phase behaviour, and clearance. Ligand identity, conjugation site, and surface density should be assessed with matched non-targeted controls (Guo et al., 2026; Kang, 2026; Luo et al., 2025; Mao et al., 2025; Tornesello et al., 2017; Fletcher et al., 2026; Majima et al., 2025; Fotou et al., 2026; Goel et al., 2026; Gong et al., 2025; Yuan et al., 2026; Ramamurthi et al., 2021; Li et al., 2024; Jozi et al., 2026; Machulkin et al., 2026; Pozdniakova et al., 2022; Yasin et al., 2026; Chen et al., 2026; Yang et al., 2025; Luo et al., 2026). The administration route should follow the product objective: intravenous delivery for systemic or heat-triggered access and image-guided local injection for depot formation (Schaal et al., 2016; Liu et al., 2012; Mukerji et al., 2016; Kelly et al., 2022; Schaal et al., 2022; Shamji et al., 2008; Shalgunov et al., 2022). Quantitative PET or SPECT, serial pharmacokinetics, and time-activity analysis can estimate lesion and organ absorbed doses with appropriate uncertainty reporting (Koo et al., 2026; Meng et al., 2026; Tartis et al., 2008; Fotou et al., 2026; Janib et al., 2013; Croteau et al., 2026; Syed et al., 2022; Kim et al., 2017; Sanad et al., 2026; Kown et al., 2002; Perkins and Frier, 2004). For local depots, three-dimensional activity coverage and local normal-tissue exposure are more informative than total lesion uptake alone.

Development should begin with a target product profile linking the administration route, lesion geometry, radionuclide properties, ELP kinetics, and required absorbed dose (Vermeulen et al., 2019; Rudd, 2026; Hu et al., 2025; Pandya et al., 2026; Koo et al., 2026; Meng et al., 2026; Shahiwala, 2026; Tian et al., 2025; Ko et al., 2026; Croteau et al., 2026; Zhang and Liu, 2026; Perkins and Frier, 2004; Yang et al., 2025). Candidate products should then undergo staged evaluation of sequence, Tt, radiochemical purity, stability, assembly state, biodistribution, imaging, dosimetry, and safety (Varanko et al., 2020; Riziotis et al., 2021; Sugiura et al., 2014; Roland et al., 2023; Chu et al., 2010; Ko et al., 2026). Predefined advancement criteria should include batch reproducibility, manufacturability, sterility, stability, and evidence that radiolabelling preserves ELP function. This approach provides a practical workflow for selecting ELP-radionuclide combinations for further development.

5 Future directions

Future studies should strengthen the direct evidence for radiolabelled ELPs. Reports should specify the ELP sequence, molecular weight, transition temperature in the final formulation, radionuclide, labelling method, and administration route. Serial biodistribution, time-integrated activity, imaging or treatment outcomes, and normal-organ exposure should be measured consistently. Common animal models, control groups, and reporting standards would improve comparison between studies. A shared database could link ELP design with pharmacokinetics and should distinguish direct radiolabelled studies from non-radioactive evidence and future proposals.

Radiolabelling should be evaluated in the final ELP product because conjugation may change phase behaviour and pharmacokinetics. Site-specific methods are preferable when random modification produces inconsistent products. Radioiodinated ELPs should be assessed for deiodination, redistribution of labelled breakdown products, and activity retained at the lesion. Radiometal-labelled ELPs require clear reporting of the chelator, conjugation conditions, radiochemical purity, and in vivo stability. Serial imaging or tissue sampling should define time-activity curves and residence times in lesions and normal organs. These measurements can show whether the radiolabelled product retains its intended function and distribution.

Each delivery method should be developed for a defined clinical purpose. Systemic formulations require measurements of blood clearance, lesion penetration and retention, and normal-organ exposure. Longer circulation does not necessarily improve tumour delivery. Thermally triggered systems require reliable temperature monitoring and controls for heating-induced changes in blood flow. Local depots require three-dimensional activity maps, assessment of needle-track leakage, and adequate coverage of irregular lesions. Clinical translation will also require scalable production, purification, endotoxin control, identity and potency specifications, rapid release testing, and stability during use. Long-term degradation, clearance, immunogenicity, repeat-dose safety, regulatory classification, and comparison with established treatments should be evaluated. Artificial intelligence-based design may become useful only when sufficiently large and consistent datasets are available.

6 Conclusion

ELPs provide a flexible scaffold for radiopharmaceutical development. Their sequence, molecular weight, transition temperature, labelling site, and assembly state can be adjusted during design. This flexibility, however, does not establish more effective or safer radionuclide delivery. Changing one feature may also alter solubility, assembly, clearance, or label stability. The final radiolabelled product must therefore be evaluated directly.

Direct evidence for ELP radiopharmaceuticals remains limited and comes mainly from local or intratumoural depot studies. These studies support prolonged local retention of radioactivity. Systemic therapy and thermally triggered targeting, by contrast, rely mostly on radiotracer studies or non-radioactive ELP research. Available studies also differ in ELP design, radionuclide, administration route, tumour model, and evaluation methods. Complete spatial dose information is uncommon, and no clinical comparison has established superiority over existing carriers or local radiation methods. Claims of improved tumour uptake, lower normal-organ exposure, multimodal synergy, or personalised theranostics should therefore remain cautious.

Clinical translation will require stable radiolabelling, clinically relevant biodistribution, and reliable evaluation of lesions and normal organs. Long-term safety, immunogenicity, GMP-compatible production, batch consistency, regulatory requirements, and comparison with established treatments also require attention. Future studies should define product specifications and decision criteria before experiments begin. These criteria should cover radiochemical quality, biodistribution, safety, and practical delivery. At present, ELPs are best regarded as a promising early-stage engineering platform rather than an established clinical delivery system.

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Footnotes

Edited by: Narsimha Mamidi, University of Wisconsin-Madison, United States

Reviewed by: David González Calatayud, Autonomous University of Madrid, Spain

Guanqing Yang, Chinese Academy of Sciences (CAS), China

Statements

Conflict of interest

Author KY was employed by Gansu TCM Modern Pharmacy Engineering Research Institution Co. Ltd.

The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was partially supported by the Natural Science Foundation for Distinguished Young Scholars of Gansu Province, Grant No. 23JRRA1349; Programme of Local Science and Technology Development in Gansu Province Guided by the Central Government, Grant No. YDZX20216200001201; Western Young Scholars Programme of the Chinese Academy of Sciences, Grant No. E223221YXB; Major Science and Technology Project of Gansu Province, Grant No. 232DFA014; National Natural Science Foundation of China, Grant No. 11875061.

Author contributions

HT: Investigation, Validation, Software, Conceptualization, Writing – review and editing, Supervision, Writing – original draft, Project administration, Formal Analysis, Methodology, Data curation. KY: Project administration, Methodology, Data curation, Software, Writing – review and editing, Investigation. HL: Validation, Project administration, Writing – review and editing, Methodology, Resources, Funding acquisition, Visualization, Formal Analysis. JX: Funding acquisition, Visualization, Formal Analysis, Resources, Project administration, Data curation, Validation, Methodology, Writing – review and editing, Supervision, Conceptualization.

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Tian, H., et al. (2026). Elastin-like polypeptides in radiopharmaceutical delivery: current evidence, design principles, and translational challenges. Frontiers in Biomaterials Science, Volume 5. https://doi.org/
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Copyright © 2026 Tian, Yang, Li and Xiao.

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*Correspondence: Haidong Tian; Jianxi Xiao

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