Nanotechnology has rapidly evolved into a transformative platform in transplant medicine, offering sophisticated tools for targeted drug delivery, organ preservation, precision diagnostics, and tolerance induction. Engineered nanoparticles enable localized and sustained delivery of immunosuppressive agents while minimizing systemic toxicity, thus allowing long-standing limitations of conventional immunosuppression to be addressed. Diverse nanomedicine platforms, including liposomes, polymeric nanoparticles, dendrimers, magnetic nanoparticles, and inorganic systems, enhance drug bioavailability, reduce off-target effects, and allow integration of imaging and therapeutic functions. This review synthesized current progress in nanoparticle-enabled therapeutics, diagnostics, machine-perfusion-based delivery, gene editing, and personalized nano-immunotherapy, highlighting their potential to reduce rejection, ischemia-reperfusion injury, and chronic graft dysfunction. Insights from recent advances in magnetic nanoparticles, including superparamagnetic iron oxide nanoparticles, further underscore their emerging value in noninvasive diagnostics and immunomodulation.

Key words : Machine perfusion, Nano-immunotherapy, Nanomedicine, Nanoparticles

Introduction
Nanotechnology, defined as the engineering and application of materials at the nanometer scale, has emerged as a powerful tool for preventing, diagnosing, and treating a wide array of medical conditions.¹ In transplantation, nanoscale systems enable controlled and targeted delivery of immunosuppressive medications, advanced molecular imaging, and strategic modulation of immune pathways involved in graft rejection. Conventional immunosuppressive drugs are limited by poor solubility, variable systemic absorption, and significant toxicity. Nanocarrier platforms address these challenges by enabling localized release, prolonged circulation, and enhanced uptake into specific tissues or immune cell subsets.² In addition, nanoparticles such as superparamagnetic iron oxide nanoparticles (SPIONs) exhibit unique magnetic properties that enhance imaging contrast and support real-time monitoring of inflammatory or alloimmune processes.

Mechanisms and Rationale for Nanotechnology in Transplantation
Drug delivery of nanotechnology has advantages over conventional drug delivery. Traditional immunosuppressive therapies are hindered by unpredictable pharmacokinetics and systemic adverse effects. Nanoparticle formulations enable highly targeted drug delivery, improved solubility, and reduced off-target toxicity.² Ligand-modified and stimuli-responsive nanoparticles can enhance precision by selectively accumulating in graft tissue or activated immune cells. Hence, nanomedicine in organ transplantation could improve the efficacy of treatments, improve quality of life, and improve organ and patient survival, while allowing for decreased dosages of systemic immunosuppressive drugs for minimized toxicity and increased patient compliance. Nanomedicine can allow targeted and sustained release with controlling drug delivery.

Essential Nanoparticle Characteristics
Nanoparticle behavior is characterized by physicochemical parameters, including size, charge, hydrophobicity, and biodegradability. Particles between 1 and 100 nm are defined as nanoparticles and could be trapped in the kidney or reticuloendothelial system.³ One of the main characteristics of nanoparticles is bidirectional solubility in water and in fat, called amphiphilic characteristic of nanoparticles. Another important feature of nanoparticles is their low immunogenicity to prevent immunoreactions and their safety for allografts. Finally, they are excreted from the kidneys without structural changes. As of 2016, the following nanoparticles have been approved by the US Food and Drug Administration: proteins, micelles, metallics, liposomes, polymerics, and nanocrystals.⁴ Nanomaterials are divided into organic or inorganic nanoparticles. Organic nanoparticles include liposomes, micelles, proteins, chitosan, starch, and polymers. Inorganic nanoparticles include metals such as gold silica, and ferrofluids.⁴ The latest type is an ideal form for organ imaging, as it has negligible organ toxicity and high resolution index. Nanomaterials and their accumulation and clearance in the kidneys are strongly correlated with their size and charge.⁵ Particles larger than 100 nm are not filterable and could be secreted to the tubules through the peritubular capillaries. Nanoparticles that are between 1 to 5 nm can be freely filtrated through glomerular basement membrane, and 1-nm nanoparticles are deposited in the glycocalyx of basement membranes. Another important characteristic of nanoparticles is their shapes and charges. Although spherical nanoparticles are ideal for glomerular filtration, cylindrical shapes are tapered in the reticuloendothelial system. Nanoparticles with positive charges have a tendency to pass through the glomerular basement membrane easily, whereas nanoparticles with negative charges are repelled from the basement membrane and returned to the circulation.

Types of Nanoparticles Used in Transplantation
Liposomes encapsulate both hydrophilic and hydrophobic drugs within lipid bilayers, allowing payload protection, PEGylation (where PEG is polyethylene glycol), and controlled or stimuli-responsive release.⁶ Liposomal corticosteroids demonstrate preferential accumulation within allografts and reduce systemic steroid-related toxicity compared with free drug formulations. Polymer-based nanosystems, such as PLGA nanoparticles, polymer-drug conjugates, and micelles, permit highly predictable degradation profiles and sustained drug release.⁴ Tacrolimus-loaded PLGA nanoparticles improve T-cell suppression, stabilize drug levels, and better preserve renal function than unencapsulated tacrolimus. Dendrimers are a class of well-defined, highly branched, and symmetric nanomaterials with central cores, an inner shell, and an outer shell, capable of precisely defined loading of small molecules, nucleic acids, or targeting ligands.⁷ Their uniform structure supports applications in both imaging and immunoregulation.

Magnetic nanoparticles
Magnetic nanoparticles, including SPIONs, support externally guided drug delivery, real-time tracking, and immune modulation; SPIONs exhibit superparamagnetic behavior and generate strong T2 magnetic resonance imaging contrast, enabling sensitive detection of inflammation or graft injury. Biomimetic magnetic nanoparticles and antigen-presenting cell-mimetic nanoparticles can modulate T-cell activation and promote regulatory immune responses.⁸ Metallic and silica-based nanoparticles are also used for multimodal imaging, biosensing, and externally triggered therapeutic applications.⁴ Coating strategies, such as dextran, PEG, or silica, modulate biodistribution, reduce oxidative stress, and mitigate reticuloendothelial system sequestration in accordance with findings from SPION safety studies.^8,9 Nanotechnologies used for transplantation are depicted in Table 1 and Figure 1.

Encapsulated immunosuppressive drug delivery
Nanoparticle encapsulation of tacrolimus, mycophenolate mofetil, corticosteroids, and other immunosuppressive drugs can be fabricated as target-specific, thus reducing systemic exposure and minimizing drug toxicity.¹⁰ Silicon nitride nanochannel membranes also provide sustained immunosuppressive release.¹¹ Iron oxide-based nanoparticles can enhance cellular uptake, allowing controlled release while limiting cytotoxicity when appropriately coated. Gene therapy and CRISPR/Cas⁹ delivery Nanoparticles facilitate delivery of CRISPR/Cas⁹, siRNA, and plasmid DNA into graft tissue, enabling modulation of alloimmune pathways. Delivery of CD40-targeted constructs can induce immunosuppression; hence, this form was shown to be ideal agent for long-term graft tolerance in a preclinical model.¹²

Donor antigen-loaded nanoparticles
Nanoparticles presenting donor antigens and rapamycin generate potent tolerogenic responses. Pretransplant administration has produced durable donor-specific unresponsiveness and long-term graft acceptance.¹³ The tablet formulation offers the advantages of better palatability and more convenience for long-term use.

Nanoparticles in rejection prevention
Nanoparticles can be used in gene therapy by delivering specific genes into the graft cells; thus, such delivery can change the immunogenicity of the graft and result in reduced risk of rejection. Nanoparticles can also be used to improve bioavailability of grafts; thus, adhesion and activation of immune cells to the allograft can be reduced. The result is reduced occurrence of inflammatory reactions and rejection. Nanomaterials can mimic the surface properties of natural cells and interact with normal tissue. This interaction can further improve graft survival. Nanoparticles, as mentioned earlier, can effectively provide an application for CRISPR/CAS9 for gene editing to disrupt CD40 immunologic marker. The elimination of CD40 genes has resulted in long-term tolerance after transplant (without immunosuppressive drugs).¹⁴ The PLGA nanoparticle formulations provide an attractive alternative to the currently available tacrolimus formulation.¹⁵ The developed formulation has the potential to decrease nephrotoxicity while maintaining the immunosuppressive activity of tacrolimus. This drug delivery system may enhance the therapeutic index and clinical benefit of tacrolimus. In addition to tacrolimus, the MMF-based nanoparticle is also used for prevention of rejection in the allograft.¹⁶ Controlled, gradual release of MMF combined with nanoparticle through perfusion of the allograft, at the time of procurement and before transplant, suppressed early intragraft immune response and abrogated chronic allograft rejection. Treatment of allografts with liposomal prednisolone is preferred compared with conventional oral prednisolone therapy.¹⁷ Allograft outcomes were improved in a case of local accumulation of nanoprednisolone in the allograft. The efficacy of liposomal prednisolone to prevent allograft rejection was superior to regular oral prednisolone. Table 2 shows main advantages of liposomal prednisolone compared with conventional prednisolone.

Normothermic Machine Perfusion as a Delivery System for Nanoparticles
Normothermic machine perfusion for nanoparticle delivery to the procured organ is ideal for maximal benefit of molecular targeting and provides a unique route for direct nanoparticle delivery to the graft endothelium while avoiding first-pass clearance by the liver and spleen.¹⁸ Because normothermic machine perfusion ensures that the delivered nanoparticles only come in direct contact with the endothelium, this delivery system circumvents competition with phagocytic cells of the liver and spleen, thus substantially preventing dilution of any benefit associated with in vivo administration of molecularly targeted nanoparticles. Another benefit for nanoparticle machine perfusion is typically performed with a serum-free perfusate, which further alleviates issues associated with masking of targeting ligands by a protein barrier (protein corona). Pretransplant infusion of donor antigen as nanoparticles in association with rapamycin has been shown to promote long-term donor-specific allograft protection with establishing tolerance. This therapy would eliminate the need for life-long immunosuppression for transplant recipients. Other nanotechnologies, aside from normothermic machine perfusion, can be used for organ preservation and to reduce ischemia-reperfusion injury. Nanotherapeutics have distinct advantages in overcoming challenges for recipients, including increasing the availability of donor organs by preserving their viability, protecting grafts from ischemia-reperfusion injury, protecting grafts for immune rejection, and preventing posttransplant tumor recurrence.¹⁹ Perfusion with anti-inflammatory nanoparticle formulations or siRNA nanoparticles can reduce apoptosis, T-cell infiltration, and HLA-DR expression in donor kidneys. Among these anti-inflammatory and antioxidant agents are PEGylated bilirubin and curcumin.^20-22 Perfluorocarbon nanoparticles have characteristics to carrier oxygen as these particles have high oxygen-carrying capacity, supporting improved metabolic stability during ex vivo preservation.²³ This could prevent allograft from hypoxia.

Nanotechnology in Transplant Diagnostics and Imaging

Magnetic resonance nanoimaging
Superparamagnetic iron oxide nanoparticles provide strong T2-weighted magnetic resonance imaging contrast, enabling sensitive detection of renal inflammation, microvascular injury, and immune cell trafficking.^24,25 Their magnetic behavior, high relaxivity, and macrophage uptake profiles have been well-established in biomedical imaging.

Surface-enhanced Raman spectroscopy urine diagnostics
Silver nanoparticles enhance Raman spectroscopy signals from urinary biomarkers, supporting early noninvasive detection of graft dysfunction.²⁶ Such urine spectroscopy analysis could be used as a convenient method for rapid assessment of kidney transplant function and would be an alternative method for allograft biopsy.

Nanoparticle-based biosensing
Granzyme B-responsive nanosensors amplify rejection-associated protease activity and release fluorescent markers into urine, enabling early diagnosis of acute cellular rejection.²³ Nanoparticles conjugated with a peptide substrate specific for the serine protease granzyme B, which is produced by recipient T cells during the onset of acute cellular rejection, can be used as a precise and noninvasive biomarker of early rejection. These nanosensors preferentially accumulate in allograft tissue and are then cleaved by granzyme B; eventually, the fluorescent biosensors are filtered into the recipient’s urine. Urinalysis can then be used to discriminate the onset of rejection with high sensitivity and specificity even before pathological appearance of rejection. This method may enable routine monitoring of allograft status without the need for biopsies.

Personalized Nanomedicine in Transplantation
The advent of personalized medicine and nanomedicine together has caused advancements in organ transplantation.²⁷ Personalized medicine involves individual patient profiles, including genetic, epigenetic, and immune characteristics, to tailor specific treatment regimens. In addition, nanomedicine has progressed to the use of nanoparticles and nanotechnology, offering precise drug delivery and innovative diagnostic tools. Thus, personalized nanomedicine has the potential to enhance graft survival and to minimize adverse effects of immunosuppressive drugs. Personalized nanomedicine could improve long-term transplant and patient outcomes. Genomic and epigenomic profiling also enables individualized selection of nanoparticle formulations based on patient-specific immune activation, alloimmune risk, and drug metabolism.²⁷ Artificial intelligence integrates clinical, molecular, and nanomaterial data to optimize nanoparticle size, surface chemistry, targeting ligands, and release kinetics. This approach supports precision nano-immunosuppression and tailored therapeutic strategies.

Safety and Toxicology of Nanotechnology in Transplantation
Nanoparticle safety depends on biodegradability, clearance pathways, and interactions with immune or vascular systems. Nonmetabolizable nanoparticles may accumulate in tissues, inducing oxidative stress or triggering thrombosis. Before daily clinical application of nanotechnology in the transplant field, we should consider pH-dependent iron release of nanoparticles, reactive oxygen species generation, macrophage uptake, and coating-dependent cytotoxicity. These considerations need to be clarified with future safety studies.

Conclusions
Nanotechnology is rapidly reshaping transplant medicine, offering significant advances in targeted immunosuppression, organ preservation, molecular imaging, and tolerance induction. Integration of nanoparticle platforms with machine perfusion, CRISPR-mediated gene editing, artificial intelligence-guided personalization, and biomimetic engineering can allow the development of safe and effective therapeutic strategies. Future clinical translation will depend on ongoing efforts to bridge mechanistic insights, nanomaterial safety, and carefully designed human studies.