Engineering intrinsically radiolabeled nanoparticles for imaging and therapy: a decade of design strategies and insights

Sanchita Ghosh; Rubel Chakravarty

doi:10.1039/d6ra03415b

. 2026 Jul 3;16(35):33652–33675. doi: 10.1039/d6ra03415b

Engineering intrinsically radiolabeled nanoparticles for imaging and therapy: a decade of design strategies and insights

Sanchita Ghosh ^a,^b, Rubel Chakravarty ^a,^b,^✉

PMCID: PMC13330772 PMID: 42405137

Abstract

The convergence of nanotechnology and nuclear medicine has opened new possibilities for cancer imaging and therapy, but conventional chelator-based radiolabeling approaches often suffer from limited stability and can alter the inherent properties of nanomaterials. Intrinsic radiolabeling has emerged as a promising alternative, enabling the direct incorporation of radionuclides within the nanoparticle matrix through mechanisms such as lattice doping, isotopic substitution, coordination to structural sites, or entrapment during nanoparticle formation. In this approach, the radionuclide becomes an integral part of the material architecture, thereby improving radiochemical stability while preserving the intrinsic physicochemical properties of the nanomaterial. Emphasis is given to how rational design and synthetic strategies have evolved to address key challenges in stability, scalability, and biological performance. A range of nanoplatforms—including inorganic systems, protein-based hybrid nanoparticles, and biomaterial-assisted systems such as hydroxyapatite and polymers—are discussed to illustrate the diversity of approaches explored. Particular attention is devoted to methodologies such as in situ radiochemical incorporation, bioinspired synthesis, and microfluidic techniques, and their role in enabling precise control over nanoparticle characteristics and translational feasibility. The performance of these systems in imaging and therapy, including multimodal and combination treatment strategies, is critically examined alongside their biological behavior and pharmacokinetics. Finally, key challenges related to clinical translation, including reproducibility, large-scale production, and regulatory considerations, are discussed. Overall, this review provides a cohesive perspective on the evolving design strategies of intrinsically radiolabeled nanoparticles and highlights pathways toward their development as clinically relevant nanotheranostic agents.

Intrinsic radiolabeling embeds radionuclides directly into nanoparticle frameworks, enabling exceptional radiochemical stability, multimodal imaging, radionuclide therapy, and advanced nanotheranostic platforms through rational design.

1. Introduction

1.1. Nanotheranostics and radiolabeled nanoplatforms

Over the past two decades, the growing interplay between nanotechnology and nuclear medicine has begun to reshape how we think about cancer diagnosis and treatment.^1–3 Nanoparticles, by virtue of their tunable size, surface properties, and multifunctionality, offer a flexible platform for integrating imaging and therapeutic capabilities within a single system.^4–7 This has led to the emergence of nanotheranostics, where diagnosis and therapy are no longer treated as separate steps but as interconnected components of a unified strategy. Within this framework, radiolabeled nanoparticles have attracted considerable attention. By incorporating radionuclides into nanomaterials, it becomes possible to achieve highly sensitive imaging using modalities such as PET and SPECT, while simultaneously enabling targeted radiotherapy.^8–16 However, as the field has matured, it has become increasingly clear that the method of radiolabeling plays a central role in determining not only the stability of these systems but also their overall biological performance and translational potential.^17–20

1.2. Limitations of chelator-based radiolabeling

Most early efforts in this area relied on chelator-based approaches, where radionuclides are attached to nanoparticles through bifunctional ligands.²⁰ While this strategy is straightforward and widely used, it is not without its drawbacks.²⁰ In practice, the stability of the metal–chelator complex can be compromised under physiological conditions, leading to partial release of the radionuclide. This can affect image quality, reduce targeting efficiency, and in some cases contribute to unwanted toxicity. Another important consideration is that the introduction of chelators often alters the surface chemistry of the nanoparticle. Even subtle changes in surface charge or hydrophilicity can influence how these systems interact with biological environments, affecting circulation time, biodistribution, and cellular uptake. In addition, the multi-step nature of chelator-based functionalization can complicate synthesis and pose challenges for reproducibility and large-scale production. These limitations have prompted researchers to look for more robust and inherently stable radiolabeling strategies.^18,19

1.3. Emergence of intrinsic radiolabeling

Intrinsic radiolabeling has gradually emerged as an attractive alternative to conventional methods.^11,21 Rather than attaching radionuclides to the nanoparticle surface through chelators, this approach integrates them directly into the nanostructure, either during synthesis or through carefully designed post-synthetic steps.^22–25 Depending on the system, this can involve lattice doping (the substitution of host atoms in a crystal lattice by radionuclide atoms of comparable ionic size and charge), isomorphic substitution, or trapping within structural defects.^18,19 One of the key advantages of this strategy is that the radionuclide becomes part of the material itself, which often translates into significantly improved radiochemical stability.^18,19 At the same time, the native physicochemical properties of the nanoparticle are largely preserved, avoiding many of the issues associated with surface modification. As a result, intrinsically radiolabeled nanoparticles tend to exhibit more predictable in vivo behavior, which is a crucial requirement for both imaging and therapeutic applications.^18,19

Over the years, a wide variety of material systems—ranging from metal sulfides and noble metals to metal oxides and hybrid nanostructures—have been explored for intrinsic radiolabeling.^{22,23,26–34} These developments have not only expanded the scope of available nanoplatforms but have also deepened our understanding of the relationship between material structure and radiochemical behavior.

1.4. Scope and objectives of this review

In parallel with these broader developments, our laboratory has been engaged in the systematic exploration of intrinsically radiolabeled nanoparticles over the past decade. Starting from early proof-of-concept studies, this work has evolved toward increasingly sophisticated systems that integrate considerations of radiochemical stability, structural design, biological performance, and translational feasibility. These contributions encompass inorganic nanomaterials, protein-assisted hybrid systems, biomaterial-derived nanoparticles, and scalable synthetic approaches such as microfluidic processing.

In this review, these studies are used not merely as representative examples, but as a coherent framework for extracting broader chemical insights into intrinsic radiolabeling. Rather than providing an exhaustive catalog of published reports, the objective is to examine how radionuclide properties (ionic radius, oxidation state, and coordination preferences), host-material structure, and synthetic methodology collectively govern radionuclide incorporation, radiochemical stability, and in vivo behavior. Particular emphasis is placed on identifying structure–radiochemistry–function relationships that explain why certain material–radionuclide combinations perform more effectively than others. We discuss key synthetic approaches—including in situ incorporation, bioinspired synthesis, polymer-assisted assembly, and microfluidic methods—and analyze how these influence nanoparticle architecture, biological interactions, and therapeutic outcomes. The review further considers practical issues related to scalability, reproducibility, and regulatory translation. Through this design-oriented perspective, the article aims to provide a conceptual framework that extends beyond specific case studies and offers general principles for the rational engineering of clinically relevant intrinsically radiolabeled nanotheranostic systems.

Thus, the present review is intended to provide more than a chronological summary of individual studies. By analyzing intrinsically radiolabeled nanoparticles through the lens of materials chemistry and radiochemistry, it highlights fundamental principles governing radionuclide–host compatibility, mechanisms of structural incorporation, and the interplay between synthetic design and biological performance. These insights establish intrinsic radiolabeling as a chemistry-driven design paradigm and offer a general framework for guiding the development of next-generation nanotheranostic systems.

2. Concept and design principles of intrinsic radiolabeling

2.1. Defining intrinsic radiolabeling

Radiolabeling of nanoparticles is often discussed in terms of methodology, but at its core, it reflects how we choose to integrate radionuclides with materials. Chemically, this integration may be achieved through lattice substitution, isotopic incorporation, strong interfacial bonding, or matrix entrapment, depending on the nature of the radionuclide and the host material.³⁵ In intrinsically radiolabeled systems, the radionuclide is built into the nanoparticle itself—either during synthesis or through carefully designed post-synthetic steps.³⁵ In other words, the radionuclide is not simply “added on,” but becomes part of the material framework.³⁵ This seemingly simple shift in approach has important consequences, particularly in terms of stability and how the system behaves in biological environments (Fig. 1).³⁵

It is also important to recognize that intrinsic incorporation does not occur in a single, uniform way. Depending on the material and the radionuclide, it may involve substitution within the crystal lattice, trapping within defects, or incorporation at specific structural sites. Appreciating these differences is essential for understanding why some systems perform better than others.

In certain exceptional cases, very strong interfacial chemical bonding—such as the Au–At interaction—can yield radiochemical behavior that closely resembles intrinsic incorporation, even when the radionuclide is localized at the nanoparticle surface.³⁶

2.2. Radiochemical considerations in nanoparticle design

Designing intrinsically radiolabeled nanoparticles requires thinking beyond conventional coordination chemistry and considering how radionuclides interact with solid-state materials. In practice, this means paying attention to both chemical compatibility and structural factors. A useful starting point is the relationship between the radionuclide and the host material. Factors such as ionic radius, oxidation state, and preferred coordination environment can strongly influence whether a radionuclide can be accommodated within a given lattice.²⁰ When these parameters are well matched, incorporation tends to be more efficient and stable. When they are not, the radionuclide may occupy less favorable sites, increasing the likelihood of release under physiological conditions.

Thermodynamic considerations are equally relevant. Radionuclides that occupy energetically favorable positions within the material are less likely to migrate or leach out. At the same time, kinetic factors—such as how easily atoms can diffuse within the structure—also play a role, particularly in dynamic biological environments.²⁰ Synthesis conditions add another layer of complexity. Temperature, reaction time, and precursor chemistry can all influence how the nanoparticle forms and how the radionuclide is incorporated. In many cases, small changes in these parameters can lead to noticeable differences in stability and performance.²⁰ As a result, careful control over synthesis is not just desirable but often necessary.

2.3. Structure–radiochemistry relationships

One of the recurring lessons from work in this area is that the behavior of a radiolabeled nanoparticle is closely tied to the nature of the material itself. Different classes of nanomaterials tend to accommodate radionuclides in different ways, and these differences have practical consequences. For instance, in metal sulfide systems, radionuclides can often be incorporated directly into the lattice during nanoparticle formation, leading to relatively stable structures. Noble metal nanoparticles offer a different kind of advantage, where isotopic incorporation allows the radionuclide to become part of the metallic core without altering the overall chemistry of the system.³⁶ In contrast, metal oxides—particularly those based on lanthanides—typically rely on ionic substitution, which depends on how well the incoming radionuclide fits within the lattice.²⁷

These variations influence not only how stable the radionuclide is within the material, but also how the nanoparticle behaves in vivo. Systems that allow deeper, more uniform incorporation tend to show better resistance to leaching, while those with less favorable incorporation pathways may exhibit partial release. An important takeaway here is that radiochemical stability cannot be considered independently of materials design. It is the combination of the radionuclide and the host material—and how well they “fit” together—that ultimately determines performance.

2.4. Design paradigms for intrinsically radiolabeled nanoparticles

As the field has evolved, it has become useful to think in terms of broader design paradigms rather than individual systems. Based on work carried out over the past decade, including contributions from our laboratory, three general approaches can be identified. These are not rigid categories, but they provide a helpful way of organizing the diversity of materials and strategies that have been explored.

2.4.1. Inorganic nanoplatforms

Inorganic nanoparticles form the backbone of many intrinsically radiolabeled systems. Materials such as metal sulfides, noble metals, and metal oxides offer well-defined structures and, in many cases, a natural compatibility with specific radionuclides.^{22,26–28,32,37–39} Metal sulfides, for example, often allow for efficient incorporation of transition metal radionuclides during synthesis.²³ Noble metals provide the unique possibility of isotopic labeling, where the radioactive and non-radioactive atoms are chemically identical.³⁶ Metal oxides, particularly those involving lanthanides, offer structured lattices that can accommodate radiometals through substitution mechanisms.^26,28 These systems are generally robust and can provide excellent radiochemical stability. At the same time, their relatively inert surfaces may require additional modifications for biological applications, which introduces additional design considerations.

2.4.2. Bioinorganic hybrid systems

Incorporating biological components into nanoparticle design has proven to be an effective way of addressing some of the limitations of purely inorganic systems.^40–45 In bioinorganic hybrid systems, biomolecules—most commonly proteins—serve as templates or stabilizing agents during nanoparticle formation.^46–53 Protein-based systems, such as those using serum albumin, offer a number of practical advantages.^54–58 They provide a biocompatible environment for nanoparticle growth, can help regulate size and morphology, and often improve dispersion in physiological media. From a biological standpoint, they also introduce functionalities that can influence circulation and cellular interactions. Importantly, these systems still allow for intrinsic radiolabeling while adding a layer of biological compatibility. This combination has made them particularly attractive for applications where in vivo performance is critical.

2.4.3. Biomaterial-mediated systems

A third approach involves the use of biomaterials such as hydroxyapatite and biodegradable polymers.⁵⁹ These materials are already familiar in biomedical contexts and, in some cases, possess inherent affinities for specific metal ions. Hydroxyapatite, for instance, has a natural tendency to interact with lanthanides, making it a suitable platform for incorporating certain therapeutic radionuclides.^60–65 Its similarity to bone mineral also opens up interesting possibilities for targeted applications. Polymeric systems, meanwhile, offer flexibility in terms of composition and degradation, which can be advantageous for controlling release and clearance.⁶³ Although these systems may not always achieve the same level of structural integration as some inorganic nanoparticles, they offer clear benefits in terms of biocompatibility and potential clinical acceptance.

2.5. Key design insights and emerging directions

Looking across these different approaches, it becomes clear that intrinsic radiolabeling is not defined by a single material or method, but by a way of thinking about how radionuclides are integrated into nanostructures. The choice of system depends on multiple factors, including the properties of the radionuclide, the intended application, and practical considerations related to synthesis and scale-up. A few general insights emerge. Stronger integration of the radionuclide within the material typically leads to better stability. The match between radionuclide and host material is critical, both chemically and structurally. And, perhaps most importantly, design choices made at the synthesis stage often have lasting consequences for biological performance.

Looking ahead, there is increasing interest in developing systems that combine multiple functionalities—such as imaging and therapy—within a single intrinsically radiolabeled platform. Advances in synthesis, including microfluidic approaches, are also opening new possibilities for achieving better control and reproducibility. Taken together, these developments suggest that intrinsic radiolabeling is moving beyond a proof-of-concept stage toward a more mature design framework, where materials chemistry, radiochemistry, and biological considerations are brought together in a more deliberate and integrated way.

3. Synthetic strategies for intrinsic radiolabeling

From a practical standpoint, the diverse synthetic approaches used for intrinsic radiolabeling can be grouped into four broad categories. The first comprises one-pot or in situ radiochemical syntheses, in which the radionuclide is introduced during nanoparticle formation and becomes incorporated as the structure develops; ⁶⁴Cu-labeled CuS nanoparticles are representative of this approach.²³ The second includes post-synthetic intrinsic incorporation, where preformed nanostructures accommodate radionuclides through lattice exchange, defect-mediated uptake, or exceptionally strong interfacial bonding; ²¹¹At-labeled gold nanoparticles provide an illustrative example.³⁶ A third category encompasses biomolecule- and polymer-assisted methods, in which proteins, polymers, or biomaterials guide nanoparticle formation while simultaneously integrating radionuclides, as demonstrated by serum albumin-based and chitosan-based systems.^19,30 Finally, flow and microfluidic approaches offer precise control over mixing and reaction kinetics, enabling highly reproducible synthesis of intrinsically radiolabeled nanoparticles with engineered pharmacokinetic properties.³³ Together, these strategies constitute a versatile synthetic toolbox that can be selected according to the chemical characteristics of the radionuclide, the nature of the host material, and the intended biological application.

3.1. One-pot and in situ radiochemical synthesis

In practice, one of the most intuitive ways to achieve intrinsic radiolabeling is simply to introduce the radionuclide at the very beginning—right when the nanoparticle is forming.³⁵ In these one-pot or in situ approaches, the radioactive precursor is present alongside the other building blocks, so the nanoparticle essentially “grows around” the radionuclide (Fig. 2). What makes this approach particularly appealing is not just its simplicity, but the way it naturally favors uniform incorporation. When things go well, the radionuclide ends up embedded within the structure rather than sitting on the surface, which is exactly what one hopes to achieve for long-term stability. At the same time, avoiding additional post-synthetic steps makes the process easier to handle and, in many cases, more reproducible.

That said, this is also where a lot of the subtlety lies. Small changes in reaction conditions—how fast nucleation happens, how quickly the particles grow, even the choice of precursors—can influence where the radionuclide ends up. In our experience, achieving consistent incorporation often comes down to carefully balancing these factors rather than relying on a single “optimized” condition.³⁵ Another practical advantage is scalability.²³ Because the radiolabeling is built into the synthesis itself, it becomes more straightforward to adapt these methods to higher activity levels, which is an important step toward real applications.^23,33

3.2. Bioinspired and biomolecule-assisted synthesis

A different way of approaching the problem is to let biology do some of the work. Bioinspired methods make use of biomolecules—most often proteins—to guide nanoparticle formation.^42,66,67 Instead of forcing the system under harsh conditions, these approaches take advantage of the natural ability of biomolecules to control nucleation and stabilize small structures.⁴² Protein-based systems, especially those using serum albumin, have proven to be particularly useful in this regard.^54,68 The protein acts almost like a confined reaction space, where nanoparticle formation and radionuclide incorporation can occur under relatively mild conditions. At the same time, it brings along a set of functional groups that help keep the particles stable in aqueous and biological environments.

What we have found especially encouraging about these systems is that they often strike a good balance between radiochemical stability and biological compatibility. The nanoparticle is still intrinsically labeled, but the presence of the biomolecular scaffold seems to improve how the system behaves in practice—whether in terms of dispersion, circulation, or interaction with cells. Perhaps just as importantly, these methods tend to be quite adaptable. By tweaking conditions such as pH or protein concentration, it is possible to fine-tune both the structure and the radiolabeling efficiency, which makes this approach quite versatile.

3.3. Polymer and biomaterial-assisted synthesis

There is also a class of systems where the focus shifts from proteins to more general biomaterials and polymers.^69,70 These materials do not necessarily provide the same level of structural control as proteins, but they offer other advantages—particularly in terms of flexibility and biocompatibility.^69,70 Polymeric systems, for example, often rely on relatively simple processes such as ionotropic gelation, in which oppositely charged species (e.g., protonated chitosan and tripolyphosphate) undergo ionic crosslinking to form nanoparticles under mild aqueous conditions.^30,71–73 In such cases, radionuclides can become associated with the forming structure through a combination of physical confinement and chemical interaction. While the degree of “true” incorporation can vary, these systems can still show reasonable stability and are often easier to handle from a formulation standpoint.

Hydroxyapatite represents a particularly interesting case. Because of its natural affinity for certain metal ions, especially lanthanides, it can incorporate radionuclides in a way that feels quite intuitive—almost as if the material is “designed” for it.⁶² Its similarity to bone mineral also opens up possibilities for targeted applications that are difficult to achieve with purely inorganic nanoparticles. From a broader perspective, what makes these systems attractive is their familiarity in biomedical settings. Many of these materials are already considered biocompatible, which can lower some of the barriers when thinking about translation.

3.4. Flow and microfluidic synthesis

As interest in these systems has grown, so has the need for better control over how they are made. This is where flow-based and microfluidic approaches start to become relevant.^74–76 Compared to traditional batch synthesis, microfluidic systems offer a much tighter handle on reaction conditions. Parameters such as mixing, temperature, and reaction time can be controlled with a level of precision that is difficult to achieve otherwise. For intrinsic radiolabeling, where small variations can affect how the radionuclide is incorporated, this level of control can make a noticeable difference.^77,78 Another advantage is consistency.⁷⁸ Producing nanoparticles with uniform size and properties is not always trivial in batch systems, but microfluidic approaches tend to give more reproducible results. This becomes especially important when particle size influences biological behavior, such as clearance or tissue penetration. From a practical standpoint, continuous flow systems also suggest a pathway toward scale-up.⁷⁷ While still developing, these methods are beginning to bridge the gap between laboratory synthesis and more application-oriented production.

3.5. Chelator-free adsorption versus intrinsic incorporation

At this point, it is worth pausing to clarify a distinction that often causes confusion. Not all chelator-free systems are intrinsically radiolabeled. In many cases, radionuclides can bind directly to nanoparticle surfaces without a chelator, and while this is certainly useful, it is not the same as being truly integrated into the structure. Surface-bound radionuclides are generally more exposed and therefore more susceptible to exchange or release, especially under physiological conditions. In contrast, intrinsic incorporation tends to provide a deeper level of stability because the radionuclide is part of the material itself.

Certain systems occupy an intermediate position between conventional surface adsorption and true structural incorporation. A notable example is ²¹¹At labeling of gold nanoparticles, where astatine forms exceptionally strong Au–At interfacial bonds with substantial covalent character.³⁶ Although the radionuclide is associated with the nanoparticle surface rather than embedded within the lattice, the resulting interaction is sufficiently robust to provide radiochemical stability comparable to many intrinsically labeled systems. Such constructs may therefore be regarded as quasi-intrinsic systems that extend the practical boundaries of intrinsic radiolabeling.

3.6. Radiochemical scalability and process considerations

As these systems move closer to practical use, questions of scalability and reproducibility naturally come to the forefront. A method that works well in a small vial does not always translate directly to larger batches or higher activity levels. One of the advantages of intrinsic radiolabeling—especially in situ approaches—is that the labeling step is built into the synthesis. This reduces the number of manipulations and can simplify handling, which is always a consideration when working with radioactivity. In some cases, it also makes it easier to reach activity levels that are relevant for preclinical or even clinical studies.

At the same time, scaling up introduces its own set of challenges. Maintaining consistent incorporation of the radionuclide, controlling particle size, and ensuring reproducibility from batch to batch all become more demanding. Practical aspects, such as timing, radiation safety, and process robustness, also start to play a more prominent role. Taken together, these considerations highlight an important point: synthetic strategy is not just about making a material—it is also about making it in a way that is reliable, scalable, and ultimately usable beyond the laboratory. For clarity, the intrinsically radiolabeled nanoparticle systems developed over the past decade, along with their corresponding material platforms, radionuclides, and functional applications, are summarized in Table 1.

Table 1. Summary of intrinsically radiolabeled nanoparticle systems developed over the past decade.

System	Material platform	Radionuclide	Intrinsic labeling strategy	Imaging/therapeutic modality	Key outcomes and insights	Representative ref.
CuS nanoparticles	Inorganic (metal sulfide)	⁶⁴Cu	Lattice incorporation during nanoparticle synthesis	PET imaging	High radiochemical stability (>95%); scalable synthesis; reliable in vivo imaging and biodistribution	23
Gold nanoparticles	Noble metal	²¹¹At	Strong Au–At interfacial bonding (quasi-intrinsic chelator-free incorporation)	Targeted alpha therapy	Stable incorporation of α-emitter; high LET-induced cytotoxicity; minimal radionuclide leakage	36
HSA-based nanoparticles	Bioinorganic hybrid (protein-assisted)	⁶⁴Cu, ¹⁷⁷Lu	Protein-mediated incorporation during nanoparticle formation	PET imaging/radionuclide therapy	Enhanced biocompatibility; improved dispersion and tumor uptake; stable radiolabel retention	37 and 79
Chitosan nanoparticles	Polymeric biomaterial	Multiple radiometals (e.g., ⁶⁴Cu, ¹⁷⁷Lu)	Coordination/entrapment within polymeric matrix	Imaging and therapy (platform system)	Multi-radiometal compatibility; flexible platform design; favorable biological interaction and stability	30
Hydroxyapatite nanoparticles	Biomaterial (calcium phosphate)	¹⁷⁷Lu	Structural incorporation within mineral matrix	Radionuclide therapy	Intrinsic biocompatibility; suitability for bone-related applications; stable radiolabeling	59
Dy₂O₃ nanoparticles	Metal oxide (lanthanide-based)	Radiometal (SPECT-active)	Intrinsic incorporation within oxide lattice	Trimodal imaging (SPECT/MRI/CT)	Combined nuclear, magnetic, and X-ray contrast; true multimodal imaging capability	26
ReO_x nanoparticles (HSA-coated)	Metal oxide hybrid	¹⁸⁸Re	Intrinsic oxide incorporation during synthesis	SPECT/CT imaging + photothermal and radionuclide therapy	Integrated theranostic platform; synergistic radiotherapy and photothermal effect; stable in vivo performance	27
¹⁶⁹Yb nanoseeds	Inorganic (embedded radionuclide system)	¹⁶⁹Yb	Direct incorporation within nanoparticle matrix	Nanoscale brachytherapy	Localized radiation delivery; prolonged tumor retention; minimally invasive therapeutic strategy	28
Flow-synthesized renal-clearable nanoparticles	Controlled inorganic/polymeric systems	Radiometals (various)	Intrinsic incorporation via controlled flow synthesis	Imaging (pharmacokinetic optimization)	Narrow size distribution; reproducible synthesis; engineered renal clearance and improved safety profile	33

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4. Materials platforms for intrinsic radiolabeling

As intrinsic radiolabeling strategies have evolved, it has become increasingly evident that the choice of material is not merely a structural consideration—it fundamentally governs how radionuclides are incorporated, how stable they remain, and how the resulting system behaves in biological environments. In many respects, the progress in this field mirrors a gradual expansion in material design, where each class of nanoplatform has offered a distinct solution to the central challenge of achieving stable and functional integration of radionuclides. From this perspective, the systems developed over the past decade can be broadly understood within three overlapping material frameworks: inorganic nanoplatforms, bioinorganic hybrid systems, and biomaterial-based nanostructures.¹⁹ While these categories are not mutually exclusive, they provide a useful way to appreciate how different material choices influence both radiochemical behavior and biological performance.¹⁹

4.1. Inorganic nanoplatforms

Inorganic nanoparticles have served as the foundation for intrinsic radiolabeling, largely due to their structural robustness and well-defined physicochemical properties.¹⁹ Their ability to accommodate radionuclides within crystalline lattices or metallic cores often leads to high radiochemical stability, which is a key requirement for in vivo applications. Metal sulfide systems were among the earliest platforms to demonstrate the feasibility of intrinsic radiolabeling in a relatively straightforward manner.²³ In these systems, radionuclides can be introduced during nanoparticle formation, becoming incorporated as the structure evolves. This approach typically results in reasonably uniform distribution of the radionuclide and good stability. Over time, these systems have also been explored for their optical and photothermal properties, making them relevant for combined imaging and therapeutic applications.^26,27,77

Noble metal nanoparticles, particularly those based on gold, offer a conceptually elegant alternative through isotopic incorporation.^22,24,33 Because the radioactive and non-radioactive atoms are chemically identical, the radionuclide becomes an indistinguishable part of the metallic core. This eliminates the possibility of dissociation through chemical exchange and results in intrinsically stable systems.^22,24,33 Advances in this area have extended from simple nanoparticle formulations to more refined architectures, including ultrasmall and targeted systems tailored for specific biological applications.^22,24

Metal oxide nanoplatforms introduce yet another mode of incorporation, typically governed by ionic substitution within a crystalline lattice.²⁶ This approach is especially well suited for radiometals such as lanthanides, where compatibility in ionic radius and charge facilitates efficient incorporation.²⁶ In addition to their radiochemical advantages, many oxide systems offer complementary functionalities, including magnetic or imaging properties, which can be leveraged for multimodal applications.²⁶ In certain cases, these materials also enable more sophisticated concepts such as in situ radionuclide generation within the nanoparticle framework.²⁶

4.2. Bioinorganic hybrid systems

While inorganic systems offer structural stability, their interaction with biological environments is not always optimal. This has led to the development of bioinorganic hybrid platforms, where biological components are integrated into the nanoparticle design to improve biocompatibility, stability, and functionality. Protein-mediated systems, particularly those involving serum albumin and related glycoproteins, have emerged as versatile platforms in this context.^26–28,38 The biomolecular scaffold acts as a confined reaction environment, enabling nanoparticle formation under mild, aqueous conditions while simultaneously facilitating radionuclide incorporation.^26–28,38 The presence of functional groups within the protein matrix enhances colloidal stability and can influence biological interactions, often resulting in improved in vivo behavior compared to purely inorganic counterparts.

A particularly important evolution of this approach is the development of intrinsically radiolabeled nanoseeds for nanoscale brachytherapy, exemplified by our recent work on glycoprotein-functionalized ytterbium oxide nanoparticles incorporating ¹⁶⁹Yb.²⁸ In this system, intrinsic radiolabeling is not merely used for imaging or tracking, but forms the basis of a localized therapeutic strategy. The nanoparticles, synthesized through controlled hydrolysis of Yb³⁺ in a glycoprotein matrix, act as nanoscale analogues of conventional brachytherapy seeds. Unlike traditional millimeter-sized sources that require surgical implantation, these nanoseeds can be administered via intratumoral injection, enabling a minimally invasive approach. Importantly, their colloidal nature allows for a more uniform distribution of radioactivity within the tumor, addressing one of the key limitations of conventional brachytherapy. The intrinsic incorporation of ¹⁶⁹Yb ensures high radiochemical stability, while in vivo studies demonstrate prolonged tumor retention with minimal off-target accumulation. This combination translates into effective tumor growth inhibition with limited systemic toxicity, highlighting the potential of such systems as clinically relevant nanoscale radiation sources. More broadly, these hybrid systems illustrate how intrinsic radiolabeling can be integrated with biologically informed design, enabling platforms that are not only stable but also functionally aligned with therapeutic requirements.

4.3. Biomaterial-based nanoplatforms

In parallel with inorganic and hybrid systems, biomaterial-based platforms have emerged as an important class of intrinsically radiolabeled systems. These materials bring inherent biocompatibility and, in some cases, specific affinities for radiometals, which can be leveraged for stable incorporation.⁵⁹ Hydroxyapatite-based systems are particularly noteworthy in this regard.⁵⁹ Owing to their natural affinity for lanthanide ions, they provide a favorable environment for incorporating therapeutic radionuclides.⁵⁹ Their structural similarity to bone mineral also opens up opportunities for targeted applications in skeletal diseases. From a translational standpoint, the established biomedical use of hydroxyapatite further strengthens their appeal.

Polymeric nanoplatforms offer a different kind of flexibility. Materials such as chitosan and other biodegradable polymers allow nanoparticles to be formed through relatively simple processes, while enabling control over size, surface properties, and degradation behavior.³⁰ Although radionuclide incorporation in these systems may not always be as structurally defined as in crystalline materials, it can still be sufficiently stable for practical applications.³⁰ In addition, the ability to integrate radiolabeling with drug delivery functions provides opportunities for multifunctional therapeutic designs. Within polymer-based systems, chitosan has emerged as a particularly versatile platform for intrinsic radiolabeling, owing to its inherent ability to complex with a wide range of metal ions.³⁰ In our work, this property was exploited to develop a facile and generalizable strategy for the synthesis of intrinsically radiolabeled chitosan nanoparticles, incorporating both diagnostic and therapeutic radionuclides such as ⁶⁴Cu, ⁶⁸Ga, ⁹⁰Y, ¹⁵³Sm, ¹⁶⁶Ho, and ¹⁷⁷Lu.³⁰

In this approach, radiometal–chitosan complexation is followed by nanoparticle formation via ionotropic gelation, enabling intrinsic incorporation without the need for chelators.³⁰ Notably, the method is operationally simple, avoids harsh conditions, and is compatible with the preparation of clinically relevant activity levels. The resulting nanoparticles exhibit high radiochemical purity and stability under physiological conditions, while maintaining favorable biological characteristics such as efficient cellular uptake and minimal toxicity. An important aspect of this work is its demonstration of a multi-radiometal platform, highlighting the versatility of intrinsic radiolabeling when combined with biomaterials. This study therefore represents a key step toward developing broadly applicable, biocompatible nanotheranostic systems.

4.4. Multifunctional and composite nanoplatforms

As the field has matured, there has been a clear shift toward the development of multifunctional systems that integrate imaging and therapeutic capabilities within a single platform.²⁷ Intrinsic radiolabeling plays a central role in this evolution, as it provides a stable foundation upon which additional functionalities can be built. Composite nanoplatforms combining radiolabeling with optical, magnetic, or photothermal properties have been explored for multimodal imaging and combination therapy.²⁷ In such systems, intrinsic radiolabeling not only enables quantitative imaging but also contributes directly to therapeutic action. The concept of nanoscale brachytherapy using intrinsically radiolabeled nanoseeds represents a particularly compelling example of this integration, where the nanoparticle itself functions as both the imaging agent and the radiation source.²⁸

Beyond the material systems discussed in detail in this review, porous framework materials such as metal–organic frameworks (MOFs) and covalent organic frameworks (COFs) have recently emerged as highly versatile platforms for intrinsic radiolabeling.^80–84 Their modular architectures provide well-defined coordination environments, large internal surface areas, and tunable pore structures that enable radionuclides to be incorporated either as framework metal nodes, through isotopic substitution, or at specific binding sites within the network. These characteristics allow simultaneous integration of radiolabeling, drug encapsulation, and stimuli-responsive functions, making MOF- and COF-based systems particularly attractive for multimodal imaging and combination therapy. Although these platforms are not reviewed in depth here because the primary focus is on design strategies established through our laboratory's work, they represent an important and rapidly growing area that further illustrates the broad applicability of intrinsic radiolabeling principles.

Designing these systems requires careful balancing of structural and functional components to ensure that added complexity does not compromise stability or performance. Nevertheless, they represent an important direction for advancing nanotheranostic strategies.

4.5. Perspective

Taken together, these material platforms highlight the diversity of approaches that have been explored to achieve intrinsic radiolabeling. Rather than converging on a single optimal system, the field has moved toward a more nuanced understanding in which material choice is guided by the specific demands of the intended application. In this context, intrinsic radiolabeling can be viewed not simply as a technique, but as a design philosophy—one that integrates materials chemistry, radiochemistry, and biological considerations into a coherent framework. As new materials and radionuclides continue to emerge, this approach is likely to play an increasingly important role in shaping the next generation of nanotheranostic systems. These material-dependent trends in radiochemical integration and functionality are reflected across the systems summarized in Table 1. A comparative perspective of the different material platforms, including their strengths, limitations, and biological implications, is summarized in Table 2.

Table 2. Comparative analysis of material platforms for intrinsically radiolabeled nanoparticles developed from our lab over last decade.

Material type	Representative systems	Key strengths	Limitations	Biological behavior	Best-suited applications
Inorganic nanoparticles	CuS (⁶⁴Cu), Au (²¹¹At), Dy₂O₃, ReO_x, ¹⁶⁹Yb nanoseeds	High structural and radiochemical stability; robust intrinsic incorporation; reproducible performance	Potential long-term retention in RES organs; limited biodegradability	Predominantly hepatobiliary clearance; strong tumor retention in many systems	PET/SPECT imaging; radionuclide therapy; alpha therapy; nanoscale brachytherapy; multimodal imaging
Bioinorganic hybrid systems	HSA-based nanoparticles (⁶⁴Cu, ¹⁷⁷Lu), ReO_x (HSA-coated)	Enhanced biocompatibility; improved dispersion and circulation; favorable tumor uptake	Moderate structural rigidity compared to inorganic systems	Improved circulation time; reduced aggregation; enhanced tumor accumulation	Imaging and therapy; theranostics; targeted delivery systems
Polymeric platforms	Chitosan-based nanoparticles (multi-radiometal systems)	High compositional flexibility; multi-radiometal compatibility; tunable surface properties	Lower structural uniformity; potential variability in synthesis	Good biocompatibility; adaptable biodistribution; cellular interaction dependent on formulation	Platform technologies; combination therapy; adaptable imaging/therapy systems
Biomaterial-based systems	Hydroxyapatite nanoparticles (¹⁷⁷Lu)	Intrinsic biocompatibility; clinical relevance; compatibility with biological tissues	Lower mechanical robustness; limited control over structural uniformity	Favorable biological interaction; potential for targeted applications (e.g., bone)	Translational applications; radionuclide therapy; tissue-specific targeting
Flow-synthesized nanoparticles	Renal-clearable intrinsically radiolabeled systems	High reproducibility; controlled size distribution; tunable pharmacokinetics	Requires specialized synthesis setup; scalability optimization needed	Reduced RES uptake; partial or predominant renal clearance	Pharmacokinetic optimization; safety-focused designs; next-generation nanotheranostics

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5. Functional performance of intrinsically radiolabeled nanoparticles

The ultimate value of intrinsically radiolabeled nanoparticles depends on how realistically their radiochemical properties are translated into predictable biological behavior. Key performance metrics include blood circulation characteristics, organ biodistribution, tumor uptake, targeting efficiency, clearance pathways, radionuclide retention, toxicity, and therapeutic response. Because the radionuclide is structurally integrated within the nanoparticle, nuclear imaging can provide a more reliable representation of the fate of the nanomaterial itself, provided that radiochemical stability is maintained in vivo. In contrast, conventional chelator-based systems may be susceptible to transchelation or ligand dissociation, which can generate misleading signals arising from released radionuclides rather than from intact nanoparticles. Intrinsic radiolabeling therefore offers an important advantage by reducing this source of uncertainty and by preserving the native physicochemical characteristics that govern biological interactions.

5.1. Imaging performance: PET, SPECT, and multimodal imaging

From an imaging perspective, intrinsically radiolabeled nanoparticles have consistently demonstrated reliable performance across both PET and SPECT modalities.^32,38,39 A recurring observation in our work is the persistence of signal at the target site, with minimal background interference. This is largely a consequence of the strong association between the radionuclide and the nanoparticle, which reduces the likelihood of in vivo detachment and redistribution. In systems based on metal sulfides, protein-assisted hybrids, and metal oxides, imaging studies have shown clear tumor localization and stable signal retention over time (Fig. 3a–d).^26–28,38 This not only improves image quality but also enhances confidence in interpreting biodistribution data. In practical terms, it allows us to attribute the observed signal directly to nanoparticle behavior, rather than questioning whether it originates from free radionuclides.

The growing interest in multimodal imaging arises from the complementary strengths of different imaging techniques. Nuclear imaging modalities such as PET and SPECT provide exceptional sensitivity and quantitative information on tracer distribution, but offer limited anatomical detail. In contrast, MRI provides excellent soft-tissue contrast, whereas CT delivers high spatial resolution and electron-density-based anatomical information. Integrating these modalities within a single intrinsically radiolabeled nanoparticle enables co-localized functional and anatomical imaging using the same agent. This not only improves localization accuracy and confidence in image interpretation, but also allows a more comprehensive assessment of biodistribution, pharmacokinetics, and therapeutic response than can be achieved with any single modality alone.

As the field has progressed, there has been a natural move toward multimodal imaging. Intrinsically radiolabeled iron oxide nanoparticles, for example, enable the integration of PET with MRI, combining the sensitivity of nuclear imaging with the anatomical resolution of magnetic resonance techniques.^16,85–88 Such platforms provide a more comprehensive understanding of nanoparticle distribution and interaction within biological systems. The choice of radionuclide also plays an important role. Longer-lived isotopes such as ⁶⁴Cu and ⁶⁹Ge are particularly well suited for nanoparticle imaging, as their half-lives align with the relatively slow pharmacokinetics of nanomaterials.^32,38 This enables longitudinal imaging and a more accurate assessment of in vivo behavior.

Compared with chelator-based radiolabeling, intrinsic incorporation generally provides a more faithful correlation between imaging signal and nanoparticle biodistribution, since the radionuclide is less prone to dissociation or redistribution in vivo. This enhanced stability can improve the reliability of quantitative imaging and dosimetric analysis, particularly in systems intended for therapy or long-term tracking (Table 3).

Table 3. Key biological performance parameters for evaluating intrinsically radiolabeled nanoparticles.

Parameter	Significance
Biodistribution	Quantifies organ and tissue accumulation over time
Tumor uptake and targeting efficiency	Assesses delivery to diseased tissue
Blood circulation half-life	Reflects systemic persistence and exposure
Clearance pathway	Determines renal vs. hepatobiliary elimination
In vivo radionuclide retention	Confirms stability of the integrated label
Toxicity and biocompatibility	Evaluates acute and chronic safety
Therapeutic response	Measures efficacy in treatment applications

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5.2. Therapeutic performance

5.2.1. β⁻-emitting systems

The incorporation of β⁻-emitting radionuclides such as ¹⁷⁷Lu and ⁹⁰Y into intrinsically radiolabeled nanoparticles has enabled the development of effective radiotherapeutic platforms.^30,79 In these systems, intrinsic radiolabeling ensures that the radionuclide remains stably embedded within the nanoparticle matrix, allowing sustained and localized dose delivery. Across a range of nanoplatforms developed in our laboratory, a clear relationship is observed between nanoparticle retention at the tumor site and therapeutic efficacy.⁷⁹ Systems that exhibit prolonged tumor localization consistently demonstrate dose-dependent tumor growth inhibition, highlighting the importance of radiochemical stability in achieving effective therapy. Hybrid systems, particularly those based on protein scaffolds, often provide a favorable balance between stability and biological compatibility, while polymer-based platforms such as chitosan nanoparticles offer flexibility in incorporating multiple therapeutic radionuclides.³⁰

5.2.2. α-emitting systems and targeted alpha therapy

In parallel with β⁻-therapy, there has been growing interest in the use of α-emitting radionuclides for cancer treatment, driven by their high linear energy transfer (LET) defined as the amount of energy deposited by ionizing radiation per unit distance traveled in tissue, and their short path length in biological tissue.^89–94 These properties enable highly localized and potent cytotoxic effects, making α-therapy particularly suitable for targeting micrometastases and small tumor clusters. Our recent work on ²¹¹At-based nanoradiopharmaceuticals represents an important step in this direction. In this study, ²¹¹At was produced via cyclotron irradiation and subsequently incorporated into gold nanoparticle systems through surface adsorption, resulting in highly stable radiolabeled constructs.³⁶ The nanoparticles demonstrated excellent radiochemical stability in both phosphate-buffered saline and human serum, maintaining structural integrity over extended periods. The choice of ²¹¹At is particularly noteworthy. Unlike many α-emitters that involve complex decay chains, ²¹¹At emits a single α-particle per decay, simplifying dosimetry and reducing concerns related to redistribution of daughter radionuclides.^95–97 Moreover, its decay pathway allows simultaneous detection via X-ray emissions, enabling imaging-based tracking of the radiopharmaceutical.

The integration of α-emitting radionuclides with nanoparticle platforms also helps address some of the limitations associated with conventional radiochemistry of astatine, such as in vivo deastatination.^36,83,98,99 By leveraging the strong interaction between astatine species and noble metal surfaces, nanoparticle-based systems provide a more stable and versatile framework for targeted alpha therapy. Taken together, these studies highlight the potential of intrinsically radiolabeled nanoparticles to serve as effective carriers for α-emitters, expanding the therapeutic scope beyond conventional β-based systems.

5.2.3. Nanoscale brachytherapy

A particularly significant development arising from this work is the concept of nanoscale brachytherapy, which represents a shift in how radionuclide therapy is conceptualized. Rather than relying solely on systemic delivery, intrinsically radiolabeled nanoparticles can be used as localized radiation sources. In systems such as ¹⁶⁹Yb-based nanoseeds, nanoparticles are administered directly into the tumor, where they remain confined and deliver radiation over extended periods (Fig. 4).²⁸ The nanoscale nature of these systems enables a more uniform distribution compared to conventional brachytherapy seeds, while intrinsic radiolabeling ensures minimal radionuclide leakage. This approach not only enhances therapeutic efficacy but also offers a minimally invasive alternative to traditional brachytherapy, illustrating how intrinsic radiolabeling can enable entirely new treatment paradigms.²⁸

5.3. Multimodal imaging and combination therapy

As intrinsically radiolabeled nanoparticles have matured, one of the most natural and impactful directions has been the integration of multiple imaging and therapeutic functionalities within a single platform.^100–103 In this context, intrinsic radiolabeling offers a particularly strong advantage, as it provides a stable radiochemical foundation upon which additional modalities can be incorporated without compromising structural integrity or in vivo performance.

A clear illustration of this evolution can be seen in the development of dysprosium oxide (Dy₂O₃)-based nanoplatforms, which demonstrate the ability to bridge nuclear imaging with magnetic resonance and X-ray-based techniques.²⁶ Dysprosium, being a lanthanide with strong paramagnetic properties, is inherently suitable for MRI contrast, while its high atomic number also enables attenuation-based imaging such as CT.^104–106 When intrinsically radiolabeled, these nanoparticles extend their functionality further to include SPECT imaging, thereby enabling a trimodal imaging platform (SPECT/MRI/CT) within a single material system.²⁶ What is particularly noteworthy in these systems is not just the coexistence of multiple imaging modalities, but the coherence between them. Because the radionuclide is intrinsically incorporated, the SPECT signal corresponds directly to the nanoparticle distribution, while MRI and CT provide complementary anatomical and structural information. This convergence allows a more comprehensive and reliable assessment of biodistribution, tumor localization, and tissue interaction, which would be difficult to achieve using separately administered agents.

In parallel, rhenium oxide (ReO_x)-based nanoparticles developed in our work further highlight the potential of intrinsically radiolabeled systems for multimodal imaging combined with therapy (Fig. 5a and b).²⁷ These nanoparticles, intrinsically labeled with radionuclides such as ¹⁸⁸Re, enable high-quality SPECT/CT imaging, where the radionuclide provides functional information and the material composition supports CT contrast. Importantly, ReO_x nanoparticles also exhibit photothermal properties, allowing them to act as agents for combined radionuclide and photothermal therapy. This dual functionality introduces a synergistic therapeutic dimension. While radionuclide therapy delivers sustained radiation-induced damage at the cellular level, photothermal therapy enables rapid, localized heating upon external irradiation. The combination of these effects can enhance tumor destruction beyond what either modality could achieve independently. From a design perspective, the ability to integrate both functions within a single intrinsically radiolabeled nanoparticle simplifies formulation and ensures that both therapeutic components are delivered to the same site.

More broadly, these systems reflect a shift toward integrated theranostic platforms, where imaging and therapy are no longer treated as separate steps but as interconnected functions within a unified design. Intrinsic radiolabeling plays a central role in enabling this integration by ensuring that the radiochemical component remains stable throughout the process, allowing the additional functionalities to operate without interference. Taken together, the Dy₂O₃ and ReO_x nanoparticle systems illustrate how careful material selection, combined with intrinsic radiolabeling, can lead to platforms that are not only multifunctional but also coherent in their performance. Such designs move beyond incremental improvements and point toward a more holistic approach to nanotheranostics, where diagnosis, monitoring, and treatment can be achieved within a single, well-defined system.

5.4. Comparative performance across design paradigms

When viewed collectively, the different intrinsically radiolabeled nanoplatforms developed over the past decade reveal a clear evolution in how material design influences functional performance. Rather than converging toward a single optimal system, these studies highlight that each class of material offers a distinct set of advantages, and that the choice of platform is best guided by the intended application.

Inorganic nanoplatforms, including metal sulfides, noble metals, and metal oxides, consistently demonstrate high structural and radiochemical stability.^10,11,107 This is particularly evident in imaging applications, where these systems provide reliable and persistent signals with minimal radionuclide detachment. Their robustness also supports sustained therapeutic dose delivery, making them well suited for both imaging and radionuclide therapy. In more advanced designs, such as Dy₂O₃-based nanoparticles, inorganic systems further enable multimodal imaging, where intrinsic radiolabeling is complemented by inherent magnetic and X-ray attenuation properties.²⁶ This illustrates how structural stability can serve as a foundation for expanding functionality without compromising performance.²⁶

Bioinorganic hybrid systems introduce an additional level of complexity by incorporating biological components into the nanoparticle design. Platforms based on proteins such as serum albumin offer improved interaction with physiological environments, leading to enhanced dispersion, reduced aggregation, and, in many cases, improved tumor uptake.^30,59 These systems often represent a balance between radiochemical stability and biological compatibility, making them particularly effective in applications where circulation behavior and biodistribution are critical. Their ability to support both imaging and therapy further underscores their versatility.

Biomaterial-based platforms, including hydroxyapatite and chitosan nanoparticles, bring a different perspective by emphasizing biocompatibility, compositional flexibility, and translational relevance.^30,59 The chitosan-based systems developed in our work, for example, demonstrate the ability to incorporate a broad range of diagnostic and therapeutic radionuclides within a single platform, highlighting the potential for multi-radiometal compatibility.³⁰ While these systems may not always achieve the same level of structural rigidity as inorganic nanoparticles, they offer advantages in terms of ease of synthesis, scalability, and alignment with clinically relevant materials.

At the level of therapeutic modality, important distinctions also emerge. β^--emitting systems provide effective treatment for larger tumor volumes due to their longer penetration range, while α-emitting systems, such as those based on ²¹¹At, offer highly localized and potent cytotoxic effects suitable for micrometastatic disease.³⁶ The integration of these radionuclides into nanoparticle platforms allows their respective advantages to be more effectively harnessed, particularly when combined with material-specific properties.

Perhaps the most significant development is the emergence of systems that integrate multiple functionalities within a single platform. ReO_x-based nanoparticles, for example, combine SPECT/CT imaging with photothermal and radionuclide therapy, illustrating how intrinsic radiolabeling can serve as a unifying element in multifunctional designs.²⁷ Similarly, nanoscale brachytherapy systems based on intrinsically radiolabeled nanoseeds represent a shift toward localized and minimally invasive treatment strategies.

Taken together, these observations suggest that intrinsic radiolabeling is less about a specific material or method, and more about a design philosophy that enables meaningful integration of radiochemistry with materials science and biology. The diversity of platforms explored in this work demonstrates that different systems can be tailored to address specific clinical needs, whether the priority is imaging accuracy, therapeutic efficacy, multimodal functionality, or translational feasibility. The functional outcomes across these platforms further reinforce the structure–performance relationships summarized in Table 1. The observed differences in imaging and therapeutic performance are consistent with the strategy-dependent trends outlined in Table 4.

Table 4. Intrinsic radiolabeling strategies and their impact on functional performance of nanoparticle systems.

Radiolabeling strategy	Mechanism of incorporation	Representative systems	Key advantages	Impact on imaging/therapeutic performance	Key insight	Ref.
Lattice incorporation during synthesis	Radionuclide integrated within crystal lattice during nanoparticle formation	⁶⁴Cu–CuS nanoparticles; Dy₂O₃ nanoparticles	Very high radiochemical stability; uniform distribution of radionuclide; scalable synthesis	Reliable PET/SPECT signal; minimal radionuclide leaching; consistent biodistribution	Most robust approach for imaging applications requiring long-term stability	23 and 26
Surface interaction (chelator-free adsorption)	Strong physicochemical interaction between radionuclide and nanoparticle surface	²¹¹At–Au nanoparticles	Simple synthesis; effective for challenging radionuclides; avoids complex chelation chemistry	Stable alpha-emitter retention; highly localized therapeutic effect	Enables use of radionuclides not easily handled by conventional chelation	36
Bio-assisted intrinsic incorporation	Radionuclide incorporated during biomolecule-mediated nanoparticle formation	HSA-based nanoparticles (⁶⁴Cu, ¹⁷⁷Lu); HSA-coated ReO_x nanoparticles	Enhanced biocompatibility; improved dispersion; better interaction with biological systems	Improved tumor uptake; favorable pharmacokinetics; stable imaging and therapy	Balances radiochemical stability with biological adaptability	37 and 79
Polymeric matrix incorporation	Radionuclide coordinated or entrapped within polymeric network	Chitosan-based nanoparticles (multi-radiometal systems)	High flexibility; compatibility with multiple radionuclides; tunable surface properties	Versatile imaging and therapeutic applications; adaptable biodistribution	Suitable platform for multi-radiometal and combination therapy strategies	30
Structural incorporation in biomaterials	Radionuclide integrated within biologically relevant material matrix	¹⁷⁷Lu–hydroxyapatite nanoparticles	Intrinsic biocompatibility; compatibility with biological tissues	Stable therapeutic delivery; potential for tissue-specific applications	Aligns material chemistry with clinical relevance	59
Intrinsic oxide formation (theranostic systems)	Radionuclide incorporated within oxide matrix during nanoparticle formation	¹⁸⁸Re–ReO_x nanoparticles	Combined imaging and therapeutic functionality; stable incorporation	SPECT/CT imaging with simultaneous radionuclide and photothermal therapy	Enables true theranostic platforms with synergistic effects	27
Embedded radionuclide systems	Radionuclide directly embedded within nanoparticle matrix (seed-like systems)	¹⁶⁹Yb nanoseeds	High retention at target site; localized radiation delivery	Effective nanoscale brachytherapy; minimal systemic redistribution	Transforms nanoparticles into active radiation sources	28
Controlled flow-based synthesis	Intrinsic incorporation under continuous, controlled reaction conditions	Renal-clearable intrinsically radiolabeled nanoparticles	High reproducibility; narrow size distribution; tunable pharmacokinetics	Improved clearance (renal pathway); reduced long-term accumulation	Links synthesis control directly to biological performance	33

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6. Biological behavior and pharmacokinetics

A persistent challenge in nanoparticle-based radiopharmaceuticals is ensuring that the observed biological behavior can be interpreted with confidence. In many conventional systems, this interpretation is complicated by the possibility of radionuclide detachment, which can obscure the true relationship between nanoparticle design and in vivo performance.^108–111 Intrinsic radiolabeling addresses this limitation directly by embedding the radionuclide within the nanostructure, thereby enabling a more faithful correlation between material properties and biological outcome.^18,19 From our studies over the past decade, it is evident that when intrinsic incorporation is achieved effectively, nanoparticle systems exhibit high radiochemical stability, reproducible biodistribution, and predictable pharmacokinetics. These features are not independent; rather, they are closely linked through the structural integration of the radionuclide within the material framework. The biological behavior and pharmacokinetic characteristics of the intrinsically radiolabeled nanoparticle systems discussed in this work are summarized in Table 5.

Table 5. Biological behavior and pharmacokinetic characteristics of intrinsically radiolabeled nanoparticle systems.

System	In vitro stability	Tumor retention	Dominant clearance pathway	Off-target accumulation	Key biological insight	Ref.
CuS nanoparticles (⁶⁴Cu)	>95% stability over 24–48 h in PBS/serum	High and sustained	Predominantly hepatobiliary (RES-mediated)	Minimal bone uptake	Strong correlation between intrinsic labeling and reliable in vivo imaging	23
Gold nanoparticles (²¹¹At)	High stability in physiological media	Localized retention (target-dependent)	Limited systemic redistribution (localized systems)	Minimal off-target due to short α range	Effective stabilization of α-emitter; enables highly localized cytotoxicity	36
HSA-based nanoparticles	>90% stability in serum conditions	Moderate to high (enhanced uptake)	Mixed (circulation + RES uptake)	Reduced non-specific accumulation compared to inorganic systems	Protein corona effects improve biological interaction without compromising stability	37 and 79
Chitosan nanoparticles	>90% stability across multiple radiometals	Moderate (formulation-dependent)	Variable (size and surface dependent)	Low non-specific uptake; biocompatible profile	Flexible platform with tunable pharmacokinetics and cellular interaction	30
Hydroxyapatite nanoparticles (¹⁷⁷Lu)	High structural stability	Target-dependent (notably bone affinity)	Predominantly hepatobiliary with tissue-specific interaction	Potential skeletal localization	Material-driven targeting enhances therapeutic relevance	59
Dy₂O₃ nanoparticles	High intrinsic stability	Moderate to high	Hepatobiliary (RES-dominated)	Limited off-target signal leakage	Stable multimodal imaging platform (SPECT/MRI/CT consistency)	26
ReO_x nanoparticles (HSA-coated)	High stability in serum	High tumor retention	Hepatobiliary	Minimal non-target redistribution	Enables combined imaging and therapy with stable in vivo behavior	27
¹⁶⁹Yb nanoseeds	Intrinsically stable (embedded radionuclide)	Very high (localized intratumoral retention)	Negligible systemic clearance (localized system)	Minimal systemic exposure	Effective nanoscale brachytherapy with confined radiation delivery	28
Flow-synthesized renal-clearable nanoparticles	High stability with controlled synthesis	Moderate	Partial or predominant renal clearance	Reduced liver/spleen accumulation	Demonstrates design-driven pharmacokinetics and improved safety profile	33

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6.1. In vitro stability and serum interactions

Across multiple intrinsically radiolabeled systems developed in our laboratory—including inorganic nanoparticles, protein-assisted hybrids, and polymer-based platforms—radiochemical stability in physiological media has been consistently high.^{26–28,30,38,59} In most cases, >90–95% of the incorporated radioactivity is retained over 24–48 h in phosphate-buffered saline and human serum, with negligible evidence of radionuclide release.^{26–28,30,38,59} This level of stability is particularly significant under serum conditions, where competing biomolecules can induce transchelation in conventional systems. In contrast, intrinsically labeled nanoparticles show minimal susceptibility to such processes, indicating that the radionuclide is not simply associated with the surface but is structurally integrated within the nanoparticle matrix.

Serum interactions, particularly protein corona formation, do influence nanoparticle size and surface characteristics.¹¹² However, an important and consistent observation is that these interactions do not compromise radiochemical integrity. As a result, any changes in hydrodynamic behavior or cellular interaction can be attributed to nanoparticle–protein interactions rather than instability of the radiolabel, allowing clearer interpretation of subsequent biological studies.

6.2. Biodistribution and tumor targeting

Biodistribution studies provide a more stringent test of radiochemical stability and functional performance. Across a range of systems, intrinsically radiolabeled nanoparticles exhibit reproducible in vivo profiles, with the measured activity closely reflecting nanoparticle localization. A notable feature in several systems developed in our laboratory is prolonged tumor retention, often sustained over multiple time points post-administration.^27,28 This behavior is particularly relevant for therapeutic applications, where effective dose delivery depends on sustained localization at the target site. Equally important is the absence—or minimal presence—of secondary uptake patterns associated with free radionuclides. For example, negligible accumulation in bone or other non-target tissues commonly associated with radiometal release provides strong indirect evidence of in vivo stability.^27,28 This consistency between expected and observed biodistribution reinforces the advantage of intrinsic radiolabeling.

Differences across material platforms further illustrate the role of design. Protein-assisted systems typically exhibit improved circulation and tumor uptake, while polymer-based systems such as chitosan nanoparticles demonstrate efficient cellular interaction and favorable biocompatibility.^27,28,30 These variations, when interpreted in the context of stable radiolabeling, provide meaningful insight into structure–function relationships.

6.3. Clearance pathways: renal versus hepatobiliary

Clearance behavior is a critical determinant of both safety and clinical applicability.¹¹³ For most intrinsically radiolabeled nanoparticles with sizes in the tens of nanometers, hepatobiliary clearance via the reticuloendothelial system (RES) is the dominant pathway, leading to accumulation in the liver and spleen followed by gradual elimination.^26–28,38 However, a distinct and important direction in our work has been the development of renal-clearable nanoparticles through controlled (flow-based) synthesis.³³ By precisely tuning particle size and surface characteristics, these systems achieve hydrodynamic dimensions compatible with renal filtration, enabling partial or predominant clearance through the kidneys.

This shift from RES-dominated to renal clearance is not merely a pharmacokinetic variation, but a design-driven outcome. Compared to conventional batch synthesis, flow-based approaches provide tighter control over nucleation and growth, resulting in narrower size distributions and more reproducible clearance profiles. The combination of intrinsic radiolabeling with such controlled synthesis allows accurate tracking of nanoparticle elimination over extended periods, ensuring that clearance data reflect the fate of the nanoparticle itself rather than dissociated radionuclide (Fig. 6). This is particularly important when evaluating long-term safety and organ retention.

6.4. Perspective: intrinsic versus conventional radiolabeling

Although the present work focuses on intrinsically radiolabeled systems, it is instructive to consider their performance in relation to conventional chelator-based approaches. In our experience, even well-established chelation strategies can exhibit partial in vivo instability, particularly for radiometals prone to transchelation. This often manifests as redistribution of activity to non-target tissues, complicating the interpretation of imaging and biodistribution data. Intrinsic radiolabeling addresses this limitation at a fundamental level by embedding the radionuclide within the nanoparticle structure. The resulting systems consistently demonstrate high in vitro stability (>90–95%), minimal evidence of in vivo dissociation, and biodistribution patterns that closely match nanoparticle behavior. At the same time, it is important to recognize that chelator-based approaches retain advantages in terms of synthetic simplicity and flexibility, particularly for small-molecule radiopharmaceuticals. However, for nanoparticle-based systems—especially those requiring prolonged circulation or sustained therapeutic action—intrinsic radiolabeling provides a more robust and reliable framework.

7. Translational considerations, challenges, and future perspectives

Over the past decade, intrinsically radiolabeled nanoparticles have moved well beyond the stage of conceptual curiosity. Many of the systems discussed in this review now demonstrate convincing performance in preclinical settings. However, translating these advances into clinically relevant technologies requires a different way of thinking—one that places equal emphasis on reproducibility, manufacturability, safety, and practicality. From our experience, the central challenge is not the lack of promising materials or radionuclides, but the difficulty of ensuring that these systems behave consistently and predictably outside controlled laboratory conditions. In this sense, translation is less about discovering new systems and more about refining existing ones so that they can withstand the demands of real-world application (Fig. 7).

7.1. Scale-up and manufacturing feasibility

One of the first realities encountered when moving beyond the laboratory is that a synthesis that works reliably in a small vial does not automatically translate to larger scales. Even minor variations in reaction conditions—mixing, temperature gradients, precursor addition—can lead to noticeable changes in nanoparticle size, morphology, and radionuclide incorporation. Intrinsic radiolabeling, particularly when integrated into one-pot synthesis, offers an important advantage here by reducing the number of processing steps. Fewer steps generally mean fewer opportunities for variability, which is essential when working with radioactive materials under time constraints. That said, achieving true scalability requires more than simplification. In our work, flow-based synthesis approaches have proven especially valuable.³³ By moving from batch to continuous systems, it becomes possible to control nucleation and growth with much greater precision. The resulting nanoparticles tend to show narrower size distributions and improved reproducibility—both of which are critical from a regulatory standpoint.³³

An additional benefit, often underappreciated, is operational. Continuous systems are inherently more compatible with radiochemical workflows, where timing, shielding, and automation play a significant role. In this sense, flow chemistry is not just a technical improvement—it aligns the synthesis itself with the practical realities of radiopharmaceutical production.

7.2. Clinically relevant materials and design choices

Another lesson that becomes increasingly clear with experience is that not all materials are equally suitable for translation, regardless of how well they perform in early studies. Systems built from biologically familiar or clinically accepted materials tend to encounter fewer barriers as development progresses. Protein-based systems, particularly those involving serum albumin, are a good example.¹¹⁴ Their behavior in biological environments is relatively well understood, and their compatibility with physiological systems makes them easier to rationalize from a safety perspective. At the same time, they provide a flexible framework for nanoparticle formation and radionuclide incorporation.

Similarly, materials such as hydroxyapatite benefit from an inherent connection to biological structures, particularly bone.¹¹⁵ This not only supports biocompatibility but also opens up opportunities for targeted applications where material choice itself contributes to function. Polymeric systems, including chitosan-based nanoparticles, occupy an interesting middle ground. They offer a high degree of flexibility—both in terms of composition and radionuclide compatibility—while still maintaining a foundation of biocompatibility.¹¹⁶ In our experience, such systems are particularly valuable when designing platforms intended to accommodate multiple radionuclides or therapeutic strategies. Overall, a recurring theme is that translational success is often less about novelty and more about choosing materials that already “fit” within biological and clinical expectations.

7.3. Dose considerations and safety

As systems move closer to clinical relevance, questions of dose and safety become more prominent and, in many ways, more complex. Unlike small-molecule radiopharmaceuticals, nanoparticles introduce additional variables—size, surface properties, retention time—that influence how radiation dose is distributed within the body. One of the strengths of intrinsically radiolabeled nanoparticles is their ability to deliver localized and sustained radiation, particularly in systems that exhibit prolonged tumor retention or are administered directly into the tumor. However, this same feature also requires careful consideration, as prolonged retention in non-target tissues could lead to unintended dose accumulation.

From our studies, it is clear that achieving a balance between effective tumor retention and efficient clearance is critical. Systems designed for localized therapy, such as nanoscale brachytherapy platforms, benefit from long retention at the target site. In contrast, systemically administered nanoparticles may require faster clearance to minimize off-target exposure. This is where design begins to play a more strategic role. The development of renal-clearable nanoparticles, particularly through controlled synthesis methods such as flow chemistry, represents an important step toward improving safety profiles.⁷⁵ By enabling elimination through the kidneys, these systems reduce long-term accumulation in organs such as the liver and spleen. Ultimately, safety in this context is not determined by a single parameter, but by how well the system balances retention, distribution, and clearance.

7.4. Regulatory and practical challenges

Even when a system performs well experimentally, the path to clinical translation involves navigating a complex regulatory landscape. Intrinsically radiolabeled nanoparticles sit at the intersection of radiopharmaceuticals and nanomedicine, and must therefore satisfy requirements from both domains.

From a practical standpoint, this means demonstrating:

• Consistent and reproducible synthesis.

• Well-defined physicochemical properties.

• Robust radiochemical stability.

• Predictable biodistribution and clearance.

In addition, production must be compatible with Good Manufacturing Practice (GMP) standards, which places constraints on synthesis methods, reagents, and overall process design.

Another aspect that often becomes apparent at this stage is the importance of workflow compatibility. Radiopharmaceutical production is inherently time-sensitive, and any system that requires complex or time-consuming processing steps may face practical limitations, regardless of its scientific merit. Intrinsic radiolabeling offers some advantages here by simplifying synthesis and reducing reliance on post-labeling steps. However, regulatory acceptance will ultimately depend on the ability to demonstrate consistency, safety, and clear clinical benefit.

7.5. Reproducibility and standardization

As the field continues to grow, variability between studies has become increasingly evident. Differences in synthesis conditions, particle size, and characterization methods can lead to variations in biological performance, making it difficult to compare results across different systems.¹⁹ In our experience, reproducibility is closely tied to control over synthesis parameters, particularly in systems where nucleation and growth are highly sensitive to reaction conditions. This again highlights the value of controlled approaches such as flow chemistry, which reduce variability and improve consistency. Equally important is the need for standardized characterization and reporting practices. Clear and consistent reporting of parameters such as radiochemical stability, particle size, and biodistribution profiles will be essential for advancing the field in a coherent manner.

A critical step toward broader adoption of intrinsically radiolabeled nanoparticles is the establishment of standardized characterization and reporting practices. At a minimum, studies should consistently report radiochemical yield and purity, radionuclide retention in physiologically relevant media, hydrodynamic size, and the specific analytical methods used to determine these parameters. Stability assessments should include well-defined incubation conditions in phosphate-buffered saline and serum, together with clearly stated time points and acceptance criteria. For biological studies, key biodistribution metrics, clearance pathways, and evidence of off-target radionuclide release should be documented in a consistent manner. Harmonized reporting of these parameters will facilitate meaningful comparison across laboratories, improve reproducibility, and accelerate regulatory evaluation and clinical translation.

7.6. Long-term toxicity and clearance

While short-term studies often demonstrate good biocompatibility, long-term behavior remains a critical area that requires more attention. This is particularly relevant for inorganic nanoparticles, which may persist in the body over extended periods. Intrinsic radiolabeling provides a useful tool for studying long-term biodistribution, as it allows accurate tracking of nanoparticles without interference from radionuclide release. However, more systematic studies are needed to fully understand the implications of prolonged retention in organs such as the liver and spleen. Design strategies that promote clearance—whether through size reduction, surface modification, or biodegradable materials—are likely to play an increasingly important role. The development of renal-clearable systems is especially promising in this regard, as it directly addresses concerns related to long-term accumulation.¹¹⁷

7.7. Emerging radionuclides and material systems

The landscape of radionuclides available for medical applications continues to expand, bringing new opportunities for intrinsic radiolabeling. Longer-lived PET radioisotopes, alpha emitters, and radionuclides with unique decay characteristics are enabling new imaging and therapeutic strategies.^38,39,96 At the same time, advances in materials science are providing new tools for controlling nanoparticle structure and function. The combination of these developments is likely to drive the next phase of innovation, where radionuclide choice and material design are more closely integrated.

7.8. Toward personalized nanotheranostics

Looking ahead, one of the most promising directions in this field is the development of personalized nanotheranostic systems that integrate imaging and therapy in a manner tailored to the biological characteristics of individual patients. Intrinsically radiolabeled nanoparticles are especially attractive in this context because the radionuclide is incorporated directly into the nanoparticle structure, allowing the same construct to track biodistribution, quantify radiation dose, monitor treatment response, and, when required, deliver therapeutic radiation. This close connection between material design and measurable in vivo behavior provides a powerful foundation for patient-specific medicine.

Realizing this vision will require advances in chemistry-driven design. Responsive nanomaterials that undergo controlled changes in response to pH, redox conditions, enzymes, hypoxia, or external stimuli such as light and ultrasound could enable spatiotemporal control over radionuclide retention, therapeutic activation, and nanoparticle degradation. Such systems would move beyond passive delivery and function as dynamic platforms that adapt to the tumor microenvironment.

Another important challenge is the rational selection of radionuclide–host combinations. At present, this process is largely empirical, even though compatibility is governed by well-defined chemical parameters such as ionic radius, oxidation state, coordination preferences, lattice energy, and surface energetics. Advances in computational chemistry, together with artificial intelligence (AI) and machine learning (ML), offer an opportunity to predict radionuclide incorporation, radiochemical stability, and biological performance before experimental validation, thereby reducing trial-and-error and accelerating materials discovery.

At the same time, future platforms must remain practical to manufacture and translate. Reproducible synthesis, rigorous characterization, scalable production, and standardized reporting will be essential for clinical adoption. Intrinsic radiolabeling also provides a flexible foundation for modular designs in which different radionuclides, targeting ligands, and therapeutic modalities can be combined according to specific clinical needs. Taken together, the future of intrinsically radiolabeled nanoparticles lies in creating systems that are not only stable, but also predictive, responsive, and adaptable. With continued progress in materials chemistry, computational design, and translational engineering, these platforms are well positioned to play an important role in the next generation of personalized molecular imaging and targeted therapy.

8. Summary and conclusions

Over the past decade, our understanding of intrinsically radiolabeled nanoparticles has evolved in a way that, in hindsight, feels quite natural. What began as an attempt to address specific limitations of conventional radiolabeling has gradually developed into a broader way of thinking about how radionuclides should be integrated into nanomaterials. A recurring realization throughout this work has been that radiolabeling is not merely a final step in nanoparticle preparation. When the radionuclide is introduced as an integral part of the material—rather than attached afterward—it begins to influence the system at a much deeper level. This shift, from “labeling” to “designing with the radionuclide,” has shaped much of the work discussed in this review.

Across the different systems developed in our laboratory, a consistent pattern emerges. When intrinsic incorporation is achieved effectively, the nanoparticles tend to behave in a more predictable and interpretable manner. Imaging signals are easier to trust because they reflect the nanoparticle itself. Biodistribution data become more meaningful because they are not confounded by radionuclide detachment. Therapeutic outcomes, in turn, are more closely tied to how the material is designed, rather than how well a label is retained. At the same time, it has become clear that there is no single material system that solves all problems. Inorganic nanoparticles offer a level of structural stability that is difficult to match, and this often translates into reliable radiochemical performance. Hybrid systems, particularly those involving proteins, bring a different advantage by interacting more naturally with biological environments. Biomaterial-based platforms, such as hydroxyapatite and polymeric systems like chitosan, add another layer by aligning more closely with clinically relevant materials and offering greater flexibility in design.

Rather than viewing these as competing approaches, it is perhaps more useful to see them as different tools—each suited to a particular type of problem. Much of the progress in this field has come from learning how to choose and adapt these materials based on the demands of the application, whether the priority is imaging, therapy, or translational feasibility. Another noticeable shift has been in how these systems are used. Early work largely focused on demonstrating that intrinsic radiolabeling was possible and stable. More recent efforts, however, have moved toward designing systems that do something more purposeful. Multimodal imaging platforms, combination therapies, and especially the development of nanoscale brachytherapy systems reflect a growing emphasis on function rather than feasibility. In these cases, the nanoparticle is no longer just a carrier—it becomes part of the therapeutic strategy itself.

The biological side of the story has also become clearer over time. One of the advantages of intrinsic radiolabeling is that it allows us to observe nanoparticle behavior with fewer uncertainties. This has made it easier to understand how factors such as size, surface properties, and material composition influence biodistribution and clearance. It has also highlighted the importance of designing systems that balance tumor retention with eventual clearance, particularly when considering long-term safety. Despite these advances, the path toward clinical translation remains challenging. Issues such as reproducibility, large-scale synthesis, and regulatory acceptance cannot be addressed by chemistry alone. In our experience, solutions that appear straightforward at the laboratory scale often become more complex when considered in a clinical context. This is where approaches such as flow-based synthesis and the use of clinically familiar materials begin to play an important role, as they help bridge the gap between conceptual design and practical implementation.

Looking ahead, the field seems to be moving toward greater integration. New radionuclides are expanding the possibilities for both imaging and therapy, while advances in materials science are enabling more controlled and multifunctional designs. At the same time, there is increasing interest in developing systems that can adapt to individual patient needs, bringing the idea of personalized nanotheranostics closer to reality. Perhaps the most important takeaway from this body of work is that intrinsic radiolabeling is not just a technical alternative to existing methods. It represents a way of thinking about nanoparticle design in which radiochemistry, materials science, and biology are considered together from the outset. When these elements are aligned, the resulting systems tend to be not only more stable, but also more meaningful in how they perform. In that sense, intrinsically radiolabeled nanoparticles have reached a point where they can be viewed not only as research tools, but as credible candidates for further development. The challenges that remain are significant, but so is the progress that has already been made. With continued refinement and a clear focus on practical considerations, these systems are well positioned to contribute to the next generation of radiopharmaceutical and nanotheranostic technologies.

Conflicts of interest

There are no conflicts to declare.

Acknowledgments

The authors gratefully acknowledge that research at Bhabha Atomic Research Centre (BARC) is an ongoing activity of the Department of Atomic Energy, Government of India, and is fully supported through internal funding. RC sincerely acknowledges Prof. Weibo Cai, University of Wisconsin–Madison, USA, for his invaluable mentorship during postdoctoral training, for introducing him to the field of nanomedicine, and for shaping his perspective on conducting meaningful and high-quality research. The authors also extend sincere thanks to all colleagues and collaborators for their continuous support, valuable discussions, and contributions over the years. Special thanks are due to Dr Tapas Das, Head, Radiopharmaceuticals Division, BARC, and Dr Y. K. Bhardwaj, Associate Director, Radiochemistry and Isotope Group, BARC, for their guidance, encouragement, and sustained support. RC is grateful to Dr Ashutosh Dash, Former Head, Radiopharmaceuticals Division, Bhabha Atomic Research Centre for facilitating the beginning of research on radionanotheranostics in BARC.

Data availability

This article is a review and does not include any new experimental data. All data discussed and analyzed were derived from previously published studies, which are appropriately cited in the manuscript. No primary research results, software or code have been included and no new data were generated or analyzed as part of this review.

References

Roy I. Krishnan S. Kabashin A. V. Zavestovskaya I. N. Prasad P. N. ACS Nano. 2022;16:5036–5061. doi: 10.1021/acsnano.1c10550. [DOI] [PubMed] [Google Scholar]
Wang H. Liu Q. Lan X. Jiang D. Angew. Chem. Int. Ed. 2022;61:e202111980. doi: 10.1002/anie.202111980. [DOI] [PubMed] [Google Scholar]
Wang Y. Barmin R. Mottaghy F. M. Kiessling F. Lammers T. Pallares R. M. J. Controlled Release. 2025;383:113815. doi: 10.1016/j.jconrel.2025.113815. [DOI] [PubMed] [Google Scholar]
Bjornmalm M. Thurecht K. J. Michael M. Scott A. M. Caruso F. ACS Nano. 2017;11:9594–9613. doi: 10.1021/acsnano.7b04855. [DOI] [PubMed] [Google Scholar]
Shi J. Kantoff P. W. Wooster R. Farokhzad O. C. Nat. Rev. Cancer. 2017;17:20–37. doi: 10.1038/nrc.2016.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
van der Meel R. Sulheim E. Shi Y. Kiessling F. Mulder W. J. Lammers T. Nat. Nanotechnol. 2019;14:1007–1017. doi: 10.1038/s41565-019-0567-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bhatia S. N. Chen X. Dobrovolskaia M. A. Lammers T. Nat. Rev. Cancer. 2022;22:550–556. doi: 10.1038/s41568-022-00496-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gholami Y. H. Maschmeyer R. Kuncic Z. Sci. Rep. 2019;9:14346. doi: 10.1038/s41598-019-50861-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
Varani M. Galli F. Auletta S. Signore A. Clin. Transl. Imaging. 2018;6:271–292. doi: 10.1007/s40336-018-0283-x. [DOI] [Google Scholar]
Chakravarty R. Shreya G. Ashutosh D. Weibo C. Q. J. Nucl. Med. Mol. Imag. 2017;61:181. [Google Scholar]
Sun X. Cai W. Chen X. Acc. Chem. Res. 2015;48:286–294. doi: 10.1021/ar500362y. [DOI] [PMC free article] [PubMed] [Google Scholar]
Forte E. Fiorenza D. Torino E. Costagliola di Polidoro A. Cavaliere C. Netti P. A. Salvatore M. Aiello M. J. Clin. Med. 2019;9:89. doi: 10.3390/jcm9010089. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ni D. Jiang D. Ehlerding E. B. Huang P. Cai W. Acc. Chem. Res. 2018;51:778–788. doi: 10.1021/acs.accounts.7b00635. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cheng S.-H. Yu D. Tsai H.-M. Morshed R. A. Kanojia D. Lo L.-W. Leoni L. Govind Y. Zhang L. Aboody K. S. J. Nucl. Med. 2016;57:279–284. doi: 10.2967/jnumed.115.163006. [DOI] [PMC free article] [PubMed] [Google Scholar]
Pijeira M. S. O. Viltres H. Kozempel J. Sakmár M. Vlk M. İlem-Özdemir D. Ekinci M. Srinivasan S. Rajabzadeh A. R. Ricci-Junior E. EJNMMI Radiopharm. Chem. 2022;7:8. doi: 10.1186/s41181-022-00161-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ai F. Ferreira C. A. Chen F. Cai W. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2016;8:619–630. doi: 10.1002/wnan.1386. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lamb J. Holland J. P. J. Nucl. Med. 2018;59:382–389. doi: 10.2967/jnumed.116.187419. [DOI] [PubMed] [Google Scholar]
Ghosh S. Lee S. J. Hsu J. C. Chakraborty S. Chakravarty R. Cai W. Chem. Biomed. Imaging. 2023;2:4–26. doi: 10.1021/cbmi.3c00092. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ghosh S. Liang Y. Cai W. Chakravarty R. J. Nanobiotechnol. 2025;23:407. doi: 10.1186/s12951-025-03472-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
Pellico J. Gawne P. J. de Rosales R. T. Chem. Soc. Rev. 2021;50:3355–3423. doi: 10.1039/D0CS00384K. [DOI] [PubMed] [Google Scholar]
Dai W. Zhang J. Wang Y. Jiao C. Song Z. Ma Y. Ding Y. Zhang Z. He X. Front. Toxicol. 2021;3:753316. doi: 10.3389/ftox.2021.753316. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chakravarty R. Chakraborty S. Guleria A. Shukla R. Kumar C. Vimalnath Nair K. Sarma H. D. Tyagi A. K. Dash A. Ind. Eng. Chem. Res. 2018;57:14337–14346. doi: 10.1021/acs.iecr.8b02526. [DOI] [Google Scholar]
Chakravarty R. Chakraborty S. Ningthoujam R. S. Vimalnath Nair K. Sharma K. S. Ballal A. Guleria A. Kunwar A. Sarma H. D. Vatsa R. K. Ind. Eng. Chem. Res. 2016;55:12407–12419. doi: 10.1021/acs.iecr.6b03405. [DOI] [Google Scholar]
Chakravarty R. Chakraborty S. Guleria A. Kumar C. Kunwar A. Nair K. V. Sarma H. D. Dash A. Nucl. Med. Biol. 2019;72:1–10. doi: 10.1016/j.nucmedbio.2019.05.005. [DOI] [PubMed] [Google Scholar]
Krekorian M. Sandker G. G. Cortenbach K. R. Tagit O. van Riessen N. K. Raavé R. Srinivas M. Figdor C. G. Heskamp S. Aarntzen E. H. Bioconjugate Chem. 2021;32:1802–1811. doi: 10.1021/acs.bioconjchem.1c00271. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ghosh S. Bhattacharya S. Barick K. C. Guleria A. Bhattacharyya K. Yadav A. K. Chakraborty A. Rakshit S. Patra S. Lawande M. ACS Appl. Mater. Interfaces. 2025;17:42767–42780. doi: 10.1021/acsami.5c08153. [DOI] [PubMed] [Google Scholar]
Ghosh S. Guleria A. Patra S. Chakraborty A. Barick K. C. Kumar C. Singh K. Rakshit S. Chakravarty R. Eur. J. Nucl. Med. Mol. Imag. 2025;52:2628–2644. doi: 10.1007/s00259-025-07074-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ghosh S. Patra S. Younis M. H. Chakraborty A. Guleria A. Gupta S. K. Singh K. Rakhshit S. Chakraborty S. Cai W. Eur. J. Nucl. Med. Mol. Imag. 2024;51:1558–1573. doi: 10.1007/s00259-024-06612-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chen F. Valdovinos H. F. Hernandez R. Goel S. Barnhart T. E. Cai W. Acta Pharmacol. Sin. 2017;38:907–913. doi: 10.1038/aps.2017.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gaikwad G. Rohra N. Kumar C. Jadhav S. Sarma H. D. Borade L. Chakraborty S. Bhagwat S. Dandekar P. Jain R. J. Drug Delivery Sci. Technol. 2021;63:102485. doi: 10.1016/j.jddst.2021.102485. [DOI] [Google Scholar]
Goel S. Chen F. Luan S. Valdovinos H. F. Shi S. Graves S. A. Ai F. Barnhart T. E. Theuer C. P. Cai W. Adv. Sci. 2016;3:1600122. doi: 10.1002/advs.201600122. [DOI] [PMC free article] [PubMed] [Google Scholar]
Guo W. Sun X. Jacobson O. Yan X. Min K. Srivatsan A. Niu G. Kiesewetter D. O. Chang J. Chen X. ACS Nano. 2015;9:488–495. doi: 10.1021/nn505660r. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chakravarty R. Sen N. Ghosh S. Sarma H. D. Guleria A. Singh K. K. Chakraborty S. Chem. Eng. J. Adv. 2023;14:100456. doi: 10.1016/j.ceja.2023.100456. [DOI] [Google Scholar]
Toro-González M. Clifford D. M. Copping R. Mirzadeh S. Rojas J. V. J. Nanopart. Res. 2018;20:238. doi: 10.1007/s11051-018-4338-8. [DOI] [Google Scholar]
Goel S. Chen F. Ehlerding E. B. Cai W. Small. 2014;10:3825–3830. doi: 10.1002/smll.201401048. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ghosh S. Banerjee D. Guleria A. Chakravarty R. Nucl. Med. Biol. 2024;138:108947. doi: 10.1016/j.nucmedbio.2024.108947. [DOI] [PubMed] [Google Scholar]
Chakravarty R. Chakraborty S. Guleria A. Kunwar A. Sarma H. D. Dash A. ChemistrySelect. 2017;2:8043–8051. doi: 10.1002/slct.201701237. [DOI] [Google Scholar]
Ghosh S. Patra S. Guleria A. Balhara A. Gupta S. K. Chakraborty A. Rakshit S. Thakare S. V. Debnath A. K. Chakraborty S. Ind. Eng. Chem. Res. 2023;62:20269–20279. doi: 10.1021/acs.iecr.3c02607. [DOI] [Google Scholar]
Patra S. Ghosh S. Singh K. Dutta B. Chakraborty A. Gamre N. Thakare S. Barick K. Rakshit S. Hassan P. J. Drug Delivery Sci. Technol. 2024;91:105204. doi: 10.1016/j.jddst.2023.105204. [DOI] [Google Scholar]
Gulati N. M. Stewart P. L. Steinmetz N. F. Mol. Pharm. 2018;15:2900–2909. doi: 10.1021/acs.molpharmaceut.8b00292. [DOI] [PMC free article] [PubMed] [Google Scholar]
Madamsetty V. S. Mukherjee A. Mukherjee S. Front. Pharmacol. 2019;10:1264. doi: 10.3389/fphar.2019.01264. [DOI] [PMC free article] [PubMed] [Google Scholar]
Mirabello G. Lenders J. J. Sommerdijk N. A. Chem. Soc. Rev. 2016;45:5085–5106. doi: 10.1039/C6CS00432F. [DOI] [PubMed] [Google Scholar]
Singh K. R. Natarajan A. Pandey S. S. ACS Appl. Bio Mater. 2023;6:4549–4571. doi: 10.1021/acsabm.3c00669. [DOI] [PubMed] [Google Scholar]
Su J. Sun H. Meng Q. Yin Q. Zhang P. Zhang Z. Yu H. Li Y. Adv. Funct. Mater. 2016;26:7495–7506. doi: 10.1002/adfm.201603381. [DOI] [Google Scholar]
Yang G. Liu Y. Wang H. Wilson R. Hui Y. Yu L. Wibowo D. Zhang C. Whittaker A. K. Middelberg A. P. Angew. Chem. 2019;131:14495–14502. doi: 10.1002/ange.201908357. [DOI] [PubMed] [Google Scholar]
Nayak S. Zhang H. Liu X. Feng S. Palo P. Nilsen-Hamilton M. Akinc M. Mallapragada S. RSC Adv. 2016;6:57048–57056. doi: 10.1039/C6RA07662A. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yang W. Guo W. Chang J. Zhang B. J. Mater. Chem. B. 2017;5:401–417. doi: 10.1039/C6TB02308H. [DOI] [PubMed] [Google Scholar]
Behrens S. Habicht W. Wagner K. Unger E. Adv. Mater. 2006;18:284–289. doi: 10.1002/adma.200501096. [DOI] [Google Scholar]
McMillan R. A. Howard J. Zaluzec N. J. Kagawa H. K. Mogul R. Li Y.-F. Paavola C. D. Trent J. D. J. Am. Chem. Soc. 2005;127:2800–2801. doi: 10.1021/ja043827s. [DOI] [PubMed] [Google Scholar]
Iwahori K. Yamashita I. J. Cluster Sci. 2007;18:358–370. doi: 10.1007/s10876-007-0126-9. [DOI] [Google Scholar]
Jackson E. Ferrari M. Cuestas-Ayllon C. Fernández-Pacheco R. Perez-Carvajal J. de la Fuente J. s. M. Grazú V. Betancor L. Langmuir. 2015;31:3687–3695. doi: 10.1021/la504978r. [DOI] [PubMed] [Google Scholar]
Devi P. S. Banerjee S. Chowdhury S. R. Kumar G. S. RSC Adv. 2012;2:11578–11585. doi: 10.1039/C2RA21053C. [DOI] [Google Scholar]
Geng X. Grove T. Z. RSC Adv. 2015;5:2062–2069. doi: 10.1039/C4RA12014K. [DOI] [Google Scholar]
Hornok V. Polymers. 2021;13:3759. doi: 10.3390/polym13213759. [DOI] [PMC free article] [PubMed] [Google Scholar]
Li C. Zhang D. Pan Y. Chen B. Polymers. 2023;15:3354. doi: 10.3390/polym15163354. [DOI] [PMC free article] [PubMed] [Google Scholar]
Dai L. Li C.-X. Liu K.-F. Su H.-J. Chen B.-Q. Zhang G.-F. He J. Lei J.-D. RSC Adv. 2015;5:15612–15620. doi: 10.1039/C4RA16346J. [DOI] [Google Scholar]
Deng G. Zhu T. Zhou L. Zhang J. Li S. Sun Z. Lai J. Meng X. Li W. Zhang P. RSC Adv. 2017;7:30717–30724. doi: 10.1039/C7RA02384G. [DOI] [Google Scholar]
Singh P. Singh H. Castro-Aceituno V. Ahn S. Kim Y. J. Yang D. C. RSC Adv. 2017;7:15397–15407. doi: 10.1039/C6RA25264H. [DOI] [Google Scholar]
Patra S. Kancharlapalli S. Chakraborty A. Singh K. Kumar C. Guleria A. Rakshit S. Damle A. Chakravarty R. Chakraborty S. Ind. Eng. Chem. Res. 2023;62:3194–3205. doi: 10.1021/acs.iecr.2c04378. [DOI] [Google Scholar]
Cawthray J. F. Creagh A. L. Haynes C. A. Orvig C. Inorg. Chem. 2015;54:1440–1445. doi: 10.1021/ic502425e. [DOI] [PubMed] [Google Scholar]
De Lama-Odría M. d. C. Valle L. J. d. Puiggalí J. Int. J. Mol. Sci. 2023;24:3446. doi: 10.3390/ijms24043446. [DOI] [PMC free article] [PubMed] [Google Scholar]
Heng C. Zhou X. Zheng X. Liu M. Wen Y. Huang H. Fan D. Hui J. Zhang X. Wei Y. Mater. Sci. Eng. C. 2018;91:556–563. doi: 10.1016/j.msec.2018.05.079. [DOI] [PubMed] [Google Scholar]
Neacsu I. A. Stoica A. E. Vasile B. S. Andronescu E. Nanomaterials. 2019;9:239. doi: 10.3390/nano9020239. [DOI] [PMC free article] [PubMed] [Google Scholar]
Al-Shahrabalee S. Q. Jaber H. A. Bioinorg. Chem. Appl. 2023;2023:7856300. doi: 10.1155/2023/7856300. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ignjatović N. L. Mančić L. Vuković M. Stojanović Z. Nikolić M. G. Škapin S. Jovanović S. Veselinović L. Uskoković V. Lazić S. Sci. Rep. 2019;9:16305. doi: 10.1038/s41598-019-52885-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
Patwardhan S. V. Manning J. R. Chiacchia M. Curr. Opin. Green Sustainable Chem. 2018;12:110–116. doi: 10.1016/j.cogsc.2018.08.004. [DOI] [Google Scholar]
Zan G. Wu Q. Adv. Mater. 2016;28:2099–2147. doi: 10.1002/adma.201503215. [DOI] [PubMed] [Google Scholar]
Meng R. Zhu H. Wang Z. Hao S. Wang B. J. Nanomater. 2022;2022:3052175. doi: 10.1155/2022/3052175. [DOI] [Google Scholar]
Li K. Liu B. Chem. Soc. Rev. 2014;43:6570–6597. doi: 10.1039/C4CS00014E. [DOI] [PubMed] [Google Scholar]
Zhang F. Lees E. Amin F. Rivera_Gil P. Yang F. Mulvaney P. Parak W. J. small. 2011;7:3113–3127. doi: 10.1002/smll.201100608. [DOI] [PubMed] [Google Scholar]
Pedroso-Santana S. Fleitas-Salazar N. Polym. Int. 2020;69:443–447. doi: 10.1002/pi.5970. [DOI] [Google Scholar]
Sacco P. Pedroso-Santana S. Kumar Y. Joly N. Martin P. Bocchetta P. Molecules. 2021;26:660. doi: 10.3390/molecules26030660. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gadziński P. Froelich A. Jadach B. Wojtyłko M. Tatarek A. Białek A. Krysztofiak J. Gackowski M. Otto F. Osmałek T. Pharmaceutics. 2023;15:108. doi: 10.3390/pharmaceutics15010108. [DOI] [PMC free article] [PubMed] [Google Scholar]
Agha A. Waheed W. Stiharu I. Nerguizian V. Destgeer G. Abu-Nada E. Alazzam A. Discover Nano. 2023;18:18. doi: 10.1186/s11671-023-03792-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
Khizar S. Zine N. Errachid A. Jaffrezic-Renault N. Elaissari A. Electrophoresis. 2022;43:819–838. doi: 10.1002/elps.202100242. [DOI] [PubMed] [Google Scholar]
Liu Y. Yang G. Hui Y. Ranaweera S. Zhao C. X. Small. 2022;18:2106580. doi: 10.1002/smll.202106580. [DOI] [PubMed] [Google Scholar]
Chakravarty R. Sen N. Ghosh S. Sarma H. D. Guleria A. Singh K. K. Chakraborty S. Chem. Eng. J. Adv. 2023;14:100456. doi: 10.1016/j.ceja.2023.100456. [DOI] [Google Scholar]
Niculescu A.-G. Chircov C. Bîrcă A. C. Grumezescu A. M. Nanomaterials. 2021;11:864. doi: 10.3390/nano11040864. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chakravarty R. Guleria A. Jadhav S. Kumar C. Debnath A. K. Sarma H. D. Chakraborty S. Ind. Eng. Chem. Res. 2020;59:22492–22500. doi: 10.1021/acs.iecr.0c03910. [DOI] [Google Scholar]
Akhmetova D. R. Tishchenko Y. A. Postovalova A. S. Rusakova V. A. Sysoev D. S. Nadporojskii M. A. Timin A. S. Shipilovskikh S. A. ACS Appl. Mater. Interfaces. 2025;18:538–552. doi: 10.1021/acsami.5c19990. [DOI] [PubMed] [Google Scholar]
Belyaev I. B. Zelepukin I. V. Tishchenko V. K. Petriev V. M. Trushina D. B. Klimentov S. M. Zavestovskaya I. N. Ivanov S. A. Kaprin A. D. Deyev S. M. Nanotechnology. 2024;35:075103. doi: 10.1088/1361-6528/ad0c74. [DOI] [PubMed] [Google Scholar]
Liang R. Li F. Chen X. Tan F. Lan T. Yang J. Liao J. Yang Y. Liu N. ACS Appl. Mater. Interfaces. 2023;15:45713–45724. doi: 10.1021/acsami.3c11098. [DOI] [PubMed] [Google Scholar]
He L. Chen X. Zhang Z. Qiu L. Lyu J. Hou R. Chen L. Zhang W. Ma Z. Zhao F. Diwu J. Liu N. Chen W. Chen L. Su J. Li F. Chai Z. Wang S. J. Am. Chem. Soc. 2026;148(8):4074–4086. doi: 10.1021/jacs.5c14889. [DOI] [PubMed] [Google Scholar]
Zhang Y. Sheng J. Zhai F. Wang X. Chen L. Shi C. Chen L. He L. Bai R. Xie J. Bioconjugate Chem. 2021;32:755–762. doi: 10.1021/acs.bioconjchem.1c00040. [DOI] [PubMed] [Google Scholar]
Karageorgou M.-A. Bouziotis P. Stiliaris E. Stamopoulos D. Nanomaterials. 2023;13:503. doi: 10.3390/nano13030503. [DOI] [PMC free article] [PubMed] [Google Scholar]
Pellico J. Ruiz-Cabello J. Herranz F. ACS Appl. Nano Mater. 2023;6:20523–20538. doi: 10.1021/acsanm.3c04269. [DOI] [Google Scholar]
Lee N. Yoo D. Ling D. Cho M. H. Hyeon T. Cheon J. Chem. Rev. 2015;115:10637–10689. doi: 10.1021/acs.chemrev.5b00112. [DOI] [PubMed] [Google Scholar]
Creţu B. E.-B. Dodi G. Shavandi A. Gardikiotis I. Şerban I. L. Balan V. Molecules. 2021;26:3437. doi: 10.3390/molecules26113437. [DOI] [PMC free article] [PubMed] [Google Scholar]
Makvandi M. Dupis E. Engle J. W. Nortier F. M. Fassbender M. E. Simon S. Birnbaum E. R. Atcher R. W. John K. D. Rixe O. Targeted Oncol. 2018;13:189–203. doi: 10.1007/s11523-018-0550-9. [DOI] [PubMed] [Google Scholar]
Zhang J. Qin S. Yang M. Zhang X. Zhang S. Yu F. Iradiology. 2023;1:245–261. doi: 10.1002/ird3.30. [DOI] [Google Scholar]
Dekempeneer Y. Keyaerts M. Krasniqi A. Puttemans J. Muyldermans S. Lahoutte T. D’huyvetter M. Devoogdt N. Expet Opin. Biol. Ther. 2016;16:1035–1047. doi: 10.1080/14712598.2016.1185412. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tafreshi N. K. Doligalski M. L. Tichacek C. J. Pandya D. N. Budzevich M. M. El-Haddad G. Khushalani N. I. Moros E. G. McLaughlin M. L. Wadas T. J. Molecules. 2019;24:4314. doi: 10.3390/molecules24234314. [DOI] [PMC free article] [PubMed] [Google Scholar]
Miederer M. Benešová-Schäfer M. Mamat C. Kaestner D. Pretze M. Michler E. Brogsitter C. Kotzerke J. Kopka K. Scheinberg D. A. Pharmaceuticals. 2024;17:76. doi: 10.3390/ph17010076. [DOI] [PMC free article] [PubMed] [Google Scholar]
Taunk N. K. Escorcia F. E. Lewis J. S. Bodei L. Cancer J. 2024;30:218–223. doi: 10.1097/PPO.0000000000000720. [DOI] [PMC free article] [PubMed] [Google Scholar]
Echigo H. Munekane M. Fuchigami T. Washiyama K. Nakamura T. Furukawa A. Chen Z. Mishiro K. Wakabayashi H. Takahashi K. Eur. J. Nucl. Med. Mol. Imag. 2025:1–12. doi: 10.1007/s00259-025-07498-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
Munekane M. Fuchigami T. Ogawa K. Anal. Sci. 2024;40:803–826. doi: 10.1007/s44211-024-00514-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zimmermann R. J. Nucl. Med. 2025;66:681–683. doi: 10.2967/jnumed.125.269699. [DOI] [PubMed] [Google Scholar]
Murata M. Kannaka K. Tatsuta S. Terasaka Y. Nonaka R. Suzuki H. Takahashi K. Uehara T. Nucl. Med. Biol. 2025:109561. doi: 10.1016/j.nucmedbio.2025.109561. [DOI] [PubMed] [Google Scholar]
Yssartier T. Liu L. Pardoue S. Le Questel J.-Y. Guérard F. Montavon G. Galland N. RSC Med. Chem. 2024;15:223–233. doi: 10.1039/D3MD00579H. [DOI] [PMC free article] [PubMed] [Google Scholar]
Calatayud D. G. Lledos M. Casarsa F. Pascu S. I. ACS Bio Med Chem Au. 2023;3:389–417. doi: 10.1021/acsbiomedchemau.3c00021. [DOI] [PMC free article] [PubMed] [Google Scholar]
Julius A. Renuka R. R. Malakondaiah S. Ramalingam S. Dharmalingam Jothinathan M. K. Srinivasan G. P. Murugan R. J. Radioanal. Nucl. Chem. 2025;334:4403–4418. doi: 10.1007/s10967-025-10233-9. [DOI] [Google Scholar]
Akhtar N. Wu P.-W. Chen C. L. Chang W.-Y. Liu R.-S. Wu C. T. Girigoswami A. Chattopadhyay S. ACS Appl. Nano Mater. 2022;5:7051–7062. doi: 10.1021/acsanm.2c01016. [DOI] [Google Scholar]
Ghosh S. Cai W. Chakravarty R. Small Sci. 2025;5:2400298. doi: 10.1002/smsc.202400298. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ricci M. Carniato F. Tei L. Camorali S. Ferrauto G. Botta M. Eur. J. Inorg. Chem. 2024;27:e202300675. doi: 10.1002/ejic.202300675. [DOI] [Google Scholar]
Jin X. Fang F. Liu J. Jiang C. Han X. Song Z. Chen J. Sun G. Lei H. Lu L. Nanoscale. 2015;7:15680–15688. doi: 10.1039/C5NR04065E. [DOI] [PubMed] [Google Scholar]
Yang M. Liu Y. Wang M. Yang C. Sun S. Zhang Q. Guo J. Wang X. Sun G. Peng Y. Chem. Eng. J. 2020;391:123562. doi: 10.1016/j.cej.2019.123562. [DOI] [Google Scholar]
Karpov T. Postovalova A. Akhmetova D. Muslimov A. R. Eletskaya E. Zyuzin M. V. Timin A. S. Chem. Mater. 2022;34:6593–6605. doi: 10.1021/acs.chemmater.2c01507. [DOI] [Google Scholar]
Damasceno A. Pijeira M. S. O. Ricci-Junior E. Alencar L. M. R. İlem-Özdemir D. Santos-Oliveira R. J. Pharm. Biomed. Anal. 2022;221:115024. doi: 10.1016/j.jpba.2022.115024. [DOI] [PubMed] [Google Scholar]
Zhao T. Liang S. H. ACS Med. Chem. Lett. 2025;16:504–507. doi: 10.1021/acsmedchemlett.5c00102. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ekinci M. Santos-oliveira R. İlem-özdemir D. J. Fac. Pharm. Ankara. 2022;46:1044–1063. [Google Scholar]
Holler J. G. Renmælmo B. Fjellaksel R. EJNMMI Radiopharm. Chem. 2022;7:2. doi: 10.1186/s41181-022-00154-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bilardo R. Traldi F. Vdovchenko A. Resmini M. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2022;14:e1788. doi: 10.1002/wnan.1788. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kaboudi N. Shayanfar A. Eur. J. Drug Metab. Pharmacokinet. 2022;47:363–369. doi: 10.1007/s13318-021-00748-3. [DOI] [PubMed] [Google Scholar]
Cho H. Jeon S. I. Ahn C.-H. Shim M. K. Kim K. Pharmaceutics. 2022;14:728. doi: 10.3390/pharmaceutics14040728. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kareem R. O. Bulut N. Kaygili O. J. Chem. Rev. 2024;6:1–26. [Google Scholar]
Pathak R. Bhatt S. Punetha V. D. Punetha M. Int. J. Biol. Macromol. 2023;253:127369. doi: 10.1016/j.ijbiomac.2023.127369. [DOI] [PubMed] [Google Scholar]
Xu M. Qi Y. Liu G. Song Y. Jiang X. Du B. ACS Nano. 2023;17:20825–20849. doi: 10.1021/acsnano.3c05853. [DOI] [PubMed] [Google Scholar]

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[cit1] Roy I. Krishnan S. Kabashin A. V. Zavestovskaya I. N. Prasad P. N. ACS Nano. 2022;16:5036–5061. doi: 10.1021/acsnano.1c10550. [DOI] [PubMed] [Google Scholar]

[cit2] Wang H. Liu Q. Lan X. Jiang D. Angew. Chem. Int. Ed. 2022;61:e202111980. doi: 10.1002/anie.202111980. [DOI] [PubMed] [Google Scholar]

[cit3] Wang Y. Barmin R. Mottaghy F. M. Kiessling F. Lammers T. Pallares R. M. J. Controlled Release. 2025;383:113815. doi: 10.1016/j.jconrel.2025.113815. [DOI] [PubMed] [Google Scholar]

[cit4] Bjornmalm M. Thurecht K. J. Michael M. Scott A. M. Caruso F. ACS Nano. 2017;11:9594–9613. doi: 10.1021/acsnano.7b04855. [DOI] [PubMed] [Google Scholar]

[cit5] Shi J. Kantoff P. W. Wooster R. Farokhzad O. C. Nat. Rev. Cancer. 2017;17:20–37. doi: 10.1038/nrc.2016.108. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit6] van der Meel R. Sulheim E. Shi Y. Kiessling F. Mulder W. J. Lammers T. Nat. Nanotechnol. 2019;14:1007–1017. doi: 10.1038/s41565-019-0567-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit7] Bhatia S. N. Chen X. Dobrovolskaia M. A. Lammers T. Nat. Rev. Cancer. 2022;22:550–556. doi: 10.1038/s41568-022-00496-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit8] Gholami Y. H. Maschmeyer R. Kuncic Z. Sci. Rep. 2019;9:14346. doi: 10.1038/s41598-019-50861-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit9] Varani M. Galli F. Auletta S. Signore A. Clin. Transl. Imaging. 2018;6:271–292. doi: 10.1007/s40336-018-0283-x. [DOI] [Google Scholar]

[cit10] Chakravarty R. Shreya G. Ashutosh D. Weibo C. Q. J. Nucl. Med. Mol. Imag. 2017;61:181. [Google Scholar]

[cit11] Sun X. Cai W. Chen X. Acc. Chem. Res. 2015;48:286–294. doi: 10.1021/ar500362y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit12] Forte E. Fiorenza D. Torino E. Costagliola di Polidoro A. Cavaliere C. Netti P. A. Salvatore M. Aiello M. J. Clin. Med. 2019;9:89. doi: 10.3390/jcm9010089. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit13] Ni D. Jiang D. Ehlerding E. B. Huang P. Cai W. Acc. Chem. Res. 2018;51:778–788. doi: 10.1021/acs.accounts.7b00635. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit14] Cheng S.-H. Yu D. Tsai H.-M. Morshed R. A. Kanojia D. Lo L.-W. Leoni L. Govind Y. Zhang L. Aboody K. S. J. Nucl. Med. 2016;57:279–284. doi: 10.2967/jnumed.115.163006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit15] Pijeira M. S. O. Viltres H. Kozempel J. Sakmár M. Vlk M. İlem-Özdemir D. Ekinci M. Srinivasan S. Rajabzadeh A. R. Ricci-Junior E. EJNMMI Radiopharm. Chem. 2022;7:8. doi: 10.1186/s41181-022-00161-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit16] Ai F. Ferreira C. A. Chen F. Cai W. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2016;8:619–630. doi: 10.1002/wnan.1386. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit17] Lamb J. Holland J. P. J. Nucl. Med. 2018;59:382–389. doi: 10.2967/jnumed.116.187419. [DOI] [PubMed] [Google Scholar]

[cit18] Ghosh S. Lee S. J. Hsu J. C. Chakraborty S. Chakravarty R. Cai W. Chem. Biomed. Imaging. 2023;2:4–26. doi: 10.1021/cbmi.3c00092. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit19] Ghosh S. Liang Y. Cai W. Chakravarty R. J. Nanobiotechnol. 2025;23:407. doi: 10.1186/s12951-025-03472-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit20] Pellico J. Gawne P. J. de Rosales R. T. Chem. Soc. Rev. 2021;50:3355–3423. doi: 10.1039/D0CS00384K. [DOI] [PubMed] [Google Scholar]

[cit21] Dai W. Zhang J. Wang Y. Jiao C. Song Z. Ma Y. Ding Y. Zhang Z. He X. Front. Toxicol. 2021;3:753316. doi: 10.3389/ftox.2021.753316. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit22] Chakravarty R. Chakraborty S. Guleria A. Shukla R. Kumar C. Vimalnath Nair K. Sarma H. D. Tyagi A. K. Dash A. Ind. Eng. Chem. Res. 2018;57:14337–14346. doi: 10.1021/acs.iecr.8b02526. [DOI] [Google Scholar]

[cit23] Chakravarty R. Chakraborty S. Ningthoujam R. S. Vimalnath Nair K. Sharma K. S. Ballal A. Guleria A. Kunwar A. Sarma H. D. Vatsa R. K. Ind. Eng. Chem. Res. 2016;55:12407–12419. doi: 10.1021/acs.iecr.6b03405. [DOI] [Google Scholar]

[cit24] Chakravarty R. Chakraborty S. Guleria A. Kumar C. Kunwar A. Nair K. V. Sarma H. D. Dash A. Nucl. Med. Biol. 2019;72:1–10. doi: 10.1016/j.nucmedbio.2019.05.005. [DOI] [PubMed] [Google Scholar]

[cit25] Krekorian M. Sandker G. G. Cortenbach K. R. Tagit O. van Riessen N. K. Raavé R. Srinivas M. Figdor C. G. Heskamp S. Aarntzen E. H. Bioconjugate Chem. 2021;32:1802–1811. doi: 10.1021/acs.bioconjchem.1c00271. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit26] Ghosh S. Bhattacharya S. Barick K. C. Guleria A. Bhattacharyya K. Yadav A. K. Chakraborty A. Rakshit S. Patra S. Lawande M. ACS Appl. Mater. Interfaces. 2025;17:42767–42780. doi: 10.1021/acsami.5c08153. [DOI] [PubMed] [Google Scholar]

[cit27] Ghosh S. Guleria A. Patra S. Chakraborty A. Barick K. C. Kumar C. Singh K. Rakshit S. Chakravarty R. Eur. J. Nucl. Med. Mol. Imag. 2025;52:2628–2644. doi: 10.1007/s00259-025-07074-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit28] Ghosh S. Patra S. Younis M. H. Chakraborty A. Guleria A. Gupta S. K. Singh K. Rakhshit S. Chakraborty S. Cai W. Eur. J. Nucl. Med. Mol. Imag. 2024;51:1558–1573. doi: 10.1007/s00259-024-06612-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit29] Chen F. Valdovinos H. F. Hernandez R. Goel S. Barnhart T. E. Cai W. Acta Pharmacol. Sin. 2017;38:907–913. doi: 10.1038/aps.2017.1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit30] Gaikwad G. Rohra N. Kumar C. Jadhav S. Sarma H. D. Borade L. Chakraborty S. Bhagwat S. Dandekar P. Jain R. J. Drug Delivery Sci. Technol. 2021;63:102485. doi: 10.1016/j.jddst.2021.102485. [DOI] [Google Scholar]

[cit31] Goel S. Chen F. Luan S. Valdovinos H. F. Shi S. Graves S. A. Ai F. Barnhart T. E. Theuer C. P. Cai W. Adv. Sci. 2016;3:1600122. doi: 10.1002/advs.201600122. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit32] Guo W. Sun X. Jacobson O. Yan X. Min K. Srivatsan A. Niu G. Kiesewetter D. O. Chang J. Chen X. ACS Nano. 2015;9:488–495. doi: 10.1021/nn505660r. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit33] Chakravarty R. Sen N. Ghosh S. Sarma H. D. Guleria A. Singh K. K. Chakraborty S. Chem. Eng. J. Adv. 2023;14:100456. doi: 10.1016/j.ceja.2023.100456. [DOI] [Google Scholar]

[cit34] Toro-González M. Clifford D. M. Copping R. Mirzadeh S. Rojas J. V. J. Nanopart. Res. 2018;20:238. doi: 10.1007/s11051-018-4338-8. [DOI] [Google Scholar]

[cit35] Goel S. Chen F. Ehlerding E. B. Cai W. Small. 2014;10:3825–3830. doi: 10.1002/smll.201401048. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit36] Ghosh S. Banerjee D. Guleria A. Chakravarty R. Nucl. Med. Biol. 2024;138:108947. doi: 10.1016/j.nucmedbio.2024.108947. [DOI] [PubMed] [Google Scholar]

[cit37] Chakravarty R. Chakraborty S. Guleria A. Kunwar A. Sarma H. D. Dash A. ChemistrySelect. 2017;2:8043–8051. doi: 10.1002/slct.201701237. [DOI] [Google Scholar]

[cit38] Ghosh S. Patra S. Guleria A. Balhara A. Gupta S. K. Chakraborty A. Rakshit S. Thakare S. V. Debnath A. K. Chakraborty S. Ind. Eng. Chem. Res. 2023;62:20269–20279. doi: 10.1021/acs.iecr.3c02607. [DOI] [Google Scholar]

[cit39] Patra S. Ghosh S. Singh K. Dutta B. Chakraborty A. Gamre N. Thakare S. Barick K. Rakshit S. Hassan P. J. Drug Delivery Sci. Technol. 2024;91:105204. doi: 10.1016/j.jddst.2023.105204. [DOI] [Google Scholar]

[cit40] Gulati N. M. Stewart P. L. Steinmetz N. F. Mol. Pharm. 2018;15:2900–2909. doi: 10.1021/acs.molpharmaceut.8b00292. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit41] Madamsetty V. S. Mukherjee A. Mukherjee S. Front. Pharmacol. 2019;10:1264. doi: 10.3389/fphar.2019.01264. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit42] Mirabello G. Lenders J. J. Sommerdijk N. A. Chem. Soc. Rev. 2016;45:5085–5106. doi: 10.1039/C6CS00432F. [DOI] [PubMed] [Google Scholar]

[cit43] Singh K. R. Natarajan A. Pandey S. S. ACS Appl. Bio Mater. 2023;6:4549–4571. doi: 10.1021/acsabm.3c00669. [DOI] [PubMed] [Google Scholar]

[cit44] Su J. Sun H. Meng Q. Yin Q. Zhang P. Zhang Z. Yu H. Li Y. Adv. Funct. Mater. 2016;26:7495–7506. doi: 10.1002/adfm.201603381. [DOI] [Google Scholar]

[cit45] Yang G. Liu Y. Wang H. Wilson R. Hui Y. Yu L. Wibowo D. Zhang C. Whittaker A. K. Middelberg A. P. Angew. Chem. 2019;131:14495–14502. doi: 10.1002/ange.201908357. [DOI] [PubMed] [Google Scholar]

[cit46] Nayak S. Zhang H. Liu X. Feng S. Palo P. Nilsen-Hamilton M. Akinc M. Mallapragada S. RSC Adv. 2016;6:57048–57056. doi: 10.1039/C6RA07662A. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit47] Yang W. Guo W. Chang J. Zhang B. J. Mater. Chem. B. 2017;5:401–417. doi: 10.1039/C6TB02308H. [DOI] [PubMed] [Google Scholar]

[cit48] Behrens S. Habicht W. Wagner K. Unger E. Adv. Mater. 2006;18:284–289. doi: 10.1002/adma.200501096. [DOI] [Google Scholar]

[cit49] McMillan R. A. Howard J. Zaluzec N. J. Kagawa H. K. Mogul R. Li Y.-F. Paavola C. D. Trent J. D. J. Am. Chem. Soc. 2005;127:2800–2801. doi: 10.1021/ja043827s. [DOI] [PubMed] [Google Scholar]

[cit50] Iwahori K. Yamashita I. J. Cluster Sci. 2007;18:358–370. doi: 10.1007/s10876-007-0126-9. [DOI] [Google Scholar]

[cit51] Jackson E. Ferrari M. Cuestas-Ayllon C. Fernández-Pacheco R. Perez-Carvajal J. de la Fuente J. s. M. Grazú V. Betancor L. Langmuir. 2015;31:3687–3695. doi: 10.1021/la504978r. [DOI] [PubMed] [Google Scholar]

[cit52] Devi P. S. Banerjee S. Chowdhury S. R. Kumar G. S. RSC Adv. 2012;2:11578–11585. doi: 10.1039/C2RA21053C. [DOI] [Google Scholar]

[cit53] Geng X. Grove T. Z. RSC Adv. 2015;5:2062–2069. doi: 10.1039/C4RA12014K. [DOI] [Google Scholar]

[cit54] Hornok V. Polymers. 2021;13:3759. doi: 10.3390/polym13213759. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit55] Li C. Zhang D. Pan Y. Chen B. Polymers. 2023;15:3354. doi: 10.3390/polym15163354. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit56] Dai L. Li C.-X. Liu K.-F. Su H.-J. Chen B.-Q. Zhang G.-F. He J. Lei J.-D. RSC Adv. 2015;5:15612–15620. doi: 10.1039/C4RA16346J. [DOI] [Google Scholar]

[cit57] Deng G. Zhu T. Zhou L. Zhang J. Li S. Sun Z. Lai J. Meng X. Li W. Zhang P. RSC Adv. 2017;7:30717–30724. doi: 10.1039/C7RA02384G. [DOI] [Google Scholar]

[cit58] Singh P. Singh H. Castro-Aceituno V. Ahn S. Kim Y. J. Yang D. C. RSC Adv. 2017;7:15397–15407. doi: 10.1039/C6RA25264H. [DOI] [Google Scholar]

[cit59] Patra S. Kancharlapalli S. Chakraborty A. Singh K. Kumar C. Guleria A. Rakshit S. Damle A. Chakravarty R. Chakraborty S. Ind. Eng. Chem. Res. 2023;62:3194–3205. doi: 10.1021/acs.iecr.2c04378. [DOI] [Google Scholar]

[cit60] Cawthray J. F. Creagh A. L. Haynes C. A. Orvig C. Inorg. Chem. 2015;54:1440–1445. doi: 10.1021/ic502425e. [DOI] [PubMed] [Google Scholar]

[cit61] De Lama-Odría M. d. C. Valle L. J. d. Puiggalí J. Int. J. Mol. Sci. 2023;24:3446. doi: 10.3390/ijms24043446. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit62] Heng C. Zhou X. Zheng X. Liu M. Wen Y. Huang H. Fan D. Hui J. Zhang X. Wei Y. Mater. Sci. Eng. C. 2018;91:556–563. doi: 10.1016/j.msec.2018.05.079. [DOI] [PubMed] [Google Scholar]

[cit63] Neacsu I. A. Stoica A. E. Vasile B. S. Andronescu E. Nanomaterials. 2019;9:239. doi: 10.3390/nano9020239. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit64] Al-Shahrabalee S. Q. Jaber H. A. Bioinorg. Chem. Appl. 2023;2023:7856300. doi: 10.1155/2023/7856300. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit65] Ignjatović N. L. Mančić L. Vuković M. Stojanović Z. Nikolić M. G. Škapin S. Jovanović S. Veselinović L. Uskoković V. Lazić S. Sci. Rep. 2019;9:16305. doi: 10.1038/s41598-019-52885-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit66] Patwardhan S. V. Manning J. R. Chiacchia M. Curr. Opin. Green Sustainable Chem. 2018;12:110–116. doi: 10.1016/j.cogsc.2018.08.004. [DOI] [Google Scholar]

[cit67] Zan G. Wu Q. Adv. Mater. 2016;28:2099–2147. doi: 10.1002/adma.201503215. [DOI] [PubMed] [Google Scholar]

[cit68] Meng R. Zhu H. Wang Z. Hao S. Wang B. J. Nanomater. 2022;2022:3052175. doi: 10.1155/2022/3052175. [DOI] [Google Scholar]

[cit69] Li K. Liu B. Chem. Soc. Rev. 2014;43:6570–6597. doi: 10.1039/C4CS00014E. [DOI] [PubMed] [Google Scholar]

[cit70] Zhang F. Lees E. Amin F. Rivera_Gil P. Yang F. Mulvaney P. Parak W. J. small. 2011;7:3113–3127. doi: 10.1002/smll.201100608. [DOI] [PubMed] [Google Scholar]

[cit71] Pedroso-Santana S. Fleitas-Salazar N. Polym. Int. 2020;69:443–447. doi: 10.1002/pi.5970. [DOI] [Google Scholar]

[cit72] Sacco P. Pedroso-Santana S. Kumar Y. Joly N. Martin P. Bocchetta P. Molecules. 2021;26:660. doi: 10.3390/molecules26030660. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit73] Gadziński P. Froelich A. Jadach B. Wojtyłko M. Tatarek A. Białek A. Krysztofiak J. Gackowski M. Otto F. Osmałek T. Pharmaceutics. 2023;15:108. doi: 10.3390/pharmaceutics15010108. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit74] Agha A. Waheed W. Stiharu I. Nerguizian V. Destgeer G. Abu-Nada E. Alazzam A. Discover Nano. 2023;18:18. doi: 10.1186/s11671-023-03792-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit75] Khizar S. Zine N. Errachid A. Jaffrezic-Renault N. Elaissari A. Electrophoresis. 2022;43:819–838. doi: 10.1002/elps.202100242. [DOI] [PubMed] [Google Scholar]

[cit76] Liu Y. Yang G. Hui Y. Ranaweera S. Zhao C. X. Small. 2022;18:2106580. doi: 10.1002/smll.202106580. [DOI] [PubMed] [Google Scholar]

[cit77] Chakravarty R. Sen N. Ghosh S. Sarma H. D. Guleria A. Singh K. K. Chakraborty S. Chem. Eng. J. Adv. 2023;14:100456. doi: 10.1016/j.ceja.2023.100456. [DOI] [Google Scholar]

[cit78] Niculescu A.-G. Chircov C. Bîrcă A. C. Grumezescu A. M. Nanomaterials. 2021;11:864. doi: 10.3390/nano11040864. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit79] Chakravarty R. Guleria A. Jadhav S. Kumar C. Debnath A. K. Sarma H. D. Chakraborty S. Ind. Eng. Chem. Res. 2020;59:22492–22500. doi: 10.1021/acs.iecr.0c03910. [DOI] [Google Scholar]

[cit80] Akhmetova D. R. Tishchenko Y. A. Postovalova A. S. Rusakova V. A. Sysoev D. S. Nadporojskii M. A. Timin A. S. Shipilovskikh S. A. ACS Appl. Mater. Interfaces. 2025;18:538–552. doi: 10.1021/acsami.5c19990. [DOI] [PubMed] [Google Scholar]

[cit81] Belyaev I. B. Zelepukin I. V. Tishchenko V. K. Petriev V. M. Trushina D. B. Klimentov S. M. Zavestovskaya I. N. Ivanov S. A. Kaprin A. D. Deyev S. M. Nanotechnology. 2024;35:075103. doi: 10.1088/1361-6528/ad0c74. [DOI] [PubMed] [Google Scholar]

[cit82] Liang R. Li F. Chen X. Tan F. Lan T. Yang J. Liao J. Yang Y. Liu N. ACS Appl. Mater. Interfaces. 2023;15:45713–45724. doi: 10.1021/acsami.3c11098. [DOI] [PubMed] [Google Scholar]

[cit83] He L. Chen X. Zhang Z. Qiu L. Lyu J. Hou R. Chen L. Zhang W. Ma Z. Zhao F. Diwu J. Liu N. Chen W. Chen L. Su J. Li F. Chai Z. Wang S. J. Am. Chem. Soc. 2026;148(8):4074–4086. doi: 10.1021/jacs.5c14889. [DOI] [PubMed] [Google Scholar]

[cit84] Zhang Y. Sheng J. Zhai F. Wang X. Chen L. Shi C. Chen L. He L. Bai R. Xie J. Bioconjugate Chem. 2021;32:755–762. doi: 10.1021/acs.bioconjchem.1c00040. [DOI] [PubMed] [Google Scholar]

[cit85] Karageorgou M.-A. Bouziotis P. Stiliaris E. Stamopoulos D. Nanomaterials. 2023;13:503. doi: 10.3390/nano13030503. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit86] Pellico J. Ruiz-Cabello J. Herranz F. ACS Appl. Nano Mater. 2023;6:20523–20538. doi: 10.1021/acsanm.3c04269. [DOI] [Google Scholar]

[cit87] Lee N. Yoo D. Ling D. Cho M. H. Hyeon T. Cheon J. Chem. Rev. 2015;115:10637–10689. doi: 10.1021/acs.chemrev.5b00112. [DOI] [PubMed] [Google Scholar]

[cit88] Creţu B. E.-B. Dodi G. Shavandi A. Gardikiotis I. Şerban I. L. Balan V. Molecules. 2021;26:3437. doi: 10.3390/molecules26113437. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit89] Makvandi M. Dupis E. Engle J. W. Nortier F. M. Fassbender M. E. Simon S. Birnbaum E. R. Atcher R. W. John K. D. Rixe O. Targeted Oncol. 2018;13:189–203. doi: 10.1007/s11523-018-0550-9. [DOI] [PubMed] [Google Scholar]

[cit90] Zhang J. Qin S. Yang M. Zhang X. Zhang S. Yu F. Iradiology. 2023;1:245–261. doi: 10.1002/ird3.30. [DOI] [Google Scholar]

[cit91] Dekempeneer Y. Keyaerts M. Krasniqi A. Puttemans J. Muyldermans S. Lahoutte T. D’huyvetter M. Devoogdt N. Expet Opin. Biol. Ther. 2016;16:1035–1047. doi: 10.1080/14712598.2016.1185412. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit92] Tafreshi N. K. Doligalski M. L. Tichacek C. J. Pandya D. N. Budzevich M. M. El-Haddad G. Khushalani N. I. Moros E. G. McLaughlin M. L. Wadas T. J. Molecules. 2019;24:4314. doi: 10.3390/molecules24234314. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit93] Miederer M. Benešová-Schäfer M. Mamat C. Kaestner D. Pretze M. Michler E. Brogsitter C. Kotzerke J. Kopka K. Scheinberg D. A. Pharmaceuticals. 2024;17:76. doi: 10.3390/ph17010076. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit94] Taunk N. K. Escorcia F. E. Lewis J. S. Bodei L. Cancer J. 2024;30:218–223. doi: 10.1097/PPO.0000000000000720. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit95] Echigo H. Munekane M. Fuchigami T. Washiyama K. Nakamura T. Furukawa A. Chen Z. Mishiro K. Wakabayashi H. Takahashi K. Eur. J. Nucl. Med. Mol. Imag. 2025:1–12. doi: 10.1007/s00259-025-07498-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit96] Munekane M. Fuchigami T. Ogawa K. Anal. Sci. 2024;40:803–826. doi: 10.1007/s44211-024-00514-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit97] Zimmermann R. J. Nucl. Med. 2025;66:681–683. doi: 10.2967/jnumed.125.269699. [DOI] [PubMed] [Google Scholar]

[cit98] Murata M. Kannaka K. Tatsuta S. Terasaka Y. Nonaka R. Suzuki H. Takahashi K. Uehara T. Nucl. Med. Biol. 2025:109561. doi: 10.1016/j.nucmedbio.2025.109561. [DOI] [PubMed] [Google Scholar]

[cit99] Yssartier T. Liu L. Pardoue S. Le Questel J.-Y. Guérard F. Montavon G. Galland N. RSC Med. Chem. 2024;15:223–233. doi: 10.1039/D3MD00579H. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit100] Calatayud D. G. Lledos M. Casarsa F. Pascu S. I. ACS Bio Med Chem Au. 2023;3:389–417. doi: 10.1021/acsbiomedchemau.3c00021. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit101] Julius A. Renuka R. R. Malakondaiah S. Ramalingam S. Dharmalingam Jothinathan M. K. Srinivasan G. P. Murugan R. J. Radioanal. Nucl. Chem. 2025;334:4403–4418. doi: 10.1007/s10967-025-10233-9. [DOI] [Google Scholar]

[cit102] Akhtar N. Wu P.-W. Chen C. L. Chang W.-Y. Liu R.-S. Wu C. T. Girigoswami A. Chattopadhyay S. ACS Appl. Nano Mater. 2022;5:7051–7062. doi: 10.1021/acsanm.2c01016. [DOI] [Google Scholar]

[cit103] Ghosh S. Cai W. Chakravarty R. Small Sci. 2025;5:2400298. doi: 10.1002/smsc.202400298. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit104] Ricci M. Carniato F. Tei L. Camorali S. Ferrauto G. Botta M. Eur. J. Inorg. Chem. 2024;27:e202300675. doi: 10.1002/ejic.202300675. [DOI] [Google Scholar]

[cit105] Jin X. Fang F. Liu J. Jiang C. Han X. Song Z. Chen J. Sun G. Lei H. Lu L. Nanoscale. 2015;7:15680–15688. doi: 10.1039/C5NR04065E. [DOI] [PubMed] [Google Scholar]

[cit106] Yang M. Liu Y. Wang M. Yang C. Sun S. Zhang Q. Guo J. Wang X. Sun G. Peng Y. Chem. Eng. J. 2020;391:123562. doi: 10.1016/j.cej.2019.123562. [DOI] [Google Scholar]

[cit107] Karpov T. Postovalova A. Akhmetova D. Muslimov A. R. Eletskaya E. Zyuzin M. V. Timin A. S. Chem. Mater. 2022;34:6593–6605. doi: 10.1021/acs.chemmater.2c01507. [DOI] [Google Scholar]

[cit108] Damasceno A. Pijeira M. S. O. Ricci-Junior E. Alencar L. M. R. İlem-Özdemir D. Santos-Oliveira R. J. Pharm. Biomed. Anal. 2022;221:115024. doi: 10.1016/j.jpba.2022.115024. [DOI] [PubMed] [Google Scholar]

[cit109] Zhao T. Liang S. H. ACS Med. Chem. Lett. 2025;16:504–507. doi: 10.1021/acsmedchemlett.5c00102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit110] Ekinci M. Santos-oliveira R. İlem-özdemir D. J. Fac. Pharm. Ankara. 2022;46:1044–1063. [Google Scholar]

[cit111] Holler J. G. Renmælmo B. Fjellaksel R. EJNMMI Radiopharm. Chem. 2022;7:2. doi: 10.1186/s41181-022-00154-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit112] Bilardo R. Traldi F. Vdovchenko A. Resmini M. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2022;14:e1788. doi: 10.1002/wnan.1788. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit113] Kaboudi N. Shayanfar A. Eur. J. Drug Metab. Pharmacokinet. 2022;47:363–369. doi: 10.1007/s13318-021-00748-3. [DOI] [PubMed] [Google Scholar]

[cit114] Cho H. Jeon S. I. Ahn C.-H. Shim M. K. Kim K. Pharmaceutics. 2022;14:728. doi: 10.3390/pharmaceutics14040728. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit115] Kareem R. O. Bulut N. Kaygili O. J. Chem. Rev. 2024;6:1–26. [Google Scholar]

[cit116] Pathak R. Bhatt S. Punetha V. D. Punetha M. Int. J. Biol. Macromol. 2023;253:127369. doi: 10.1016/j.ijbiomac.2023.127369. [DOI] [PubMed] [Google Scholar]

[cit117] Xu M. Qi Y. Liu G. Song Y. Jiang X. Du B. ACS Nano. 2023;17:20825–20849. doi: 10.1021/acsnano.3c05853. [DOI] [PubMed] [Google Scholar]

PERMALINK

Engineering intrinsically radiolabeled nanoparticles for imaging and therapy: a decade of design strategies and insights

Sanchita Ghosh

Rubel Chakravarty

Abstract

1. Introduction

1.1. Nanotheranostics and radiolabeled nanoplatforms

1.2. Limitations of chelator-based radiolabeling

1.3. Emergence of intrinsic radiolabeling

1.4. Scope and objectives of this review

2. Concept and design principles of intrinsic radiolabeling

2.1. Defining intrinsic radiolabeling

Fig. 1. Schematic comparison of conventional chelator-based radiolabeling and intrinsic radiolabeling strategies.

2.2. Radiochemical considerations in nanoparticle design

2.3. Structure–radiochemistry relationships

2.4. Design paradigms for intrinsically radiolabeled nanoparticles

2.4.1. Inorganic nanoplatforms

2.4.2. Bioinorganic hybrid systems

2.4.3. Biomaterial-mediated systems

2.5. Key design insights and emerging directions

3. Synthetic strategies for intrinsic radiolabeling

3.1. One-pot and in situ radiochemical synthesis

Fig. 2. Overview of intrinsic radiolabeling strategies employed for nanoparticle synthesis.

3.2. Bioinspired and biomolecule-assisted synthesis

3.3. Polymer and biomaterial-assisted synthesis

3.4. Flow and microfluidic synthesis

3.5. Chelator-free adsorption versus intrinsic incorporation

3.6. Radiochemical scalability and process considerations

Table 1. Summary of intrinsically radiolabeled nanoparticle systems developed over the past decade.

4. Materials platforms for intrinsic radiolabeling

4.1. Inorganic nanoplatforms

4.2. Bioinorganic hybrid systems

4.3. Biomaterial-based nanoplatforms

4.4. Multifunctional and composite nanoplatforms

4.5. Perspective

Table 2. Comparative analysis of material platforms for intrinsically radiolabeled nanoparticles developed from our lab over last decade.

5. Functional performance of intrinsically radiolabeled nanoparticles

5.1. Imaging performance: PET, SPECT, and multimodal imaging

Table 3. Key biological performance parameters for evaluating intrinsically radiolabeled nanoparticles.

5.2. Therapeutic performance

5.2.1. β−-emitting systems

5.2.2. α-emitting systems and targeted alpha therapy

5.2.3. Nanoscale brachytherapy

5.3. Multimodal imaging and combination therapy

5.4. Comparative performance across design paradigms

Table 4. Intrinsic radiolabeling strategies and their impact on functional performance of nanoparticle systems.

6. Biological behavior and pharmacokinetics

Table 5. Biological behavior and pharmacokinetic characteristics of intrinsically radiolabeled nanoparticle systems.

6.1. In vitro stability and serum interactions

6.2. Biodistribution and tumor targeting

6.3. Clearance pathways: renal versus hepatobiliary

6.4. Perspective: intrinsic versus conventional radiolabeling

7. Translational considerations, challenges, and future perspectives

Fig. 7. Translational roadmap for intrinsically radiolabeled nanoparticle systems.

7.1. Scale-up and manufacturing feasibility

7.2. Clinically relevant materials and design choices

7.3. Dose considerations and safety

7.4. Regulatory and practical challenges

7.5. Reproducibility and standardization

7.6. Long-term toxicity and clearance

7.7. Emerging radionuclides and material systems

7.8. Toward personalized nanotheranostics

8. Summary and conclusions

Conflicts of interest

Acknowledgments

Data availability

References

Associated Data

Data Availability Statement

ACTIONS

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5.2.1. β⁻-emitting systems