Nanotherapeutics for solid organ transplantation: new kid on the block

Solid organ transplantation is widely regarded as a definitive and life-saving therapeutic strategy for individuals suffering from end-stage organ failure. The development of efficient immunosuppressive medicines, as well as improvement in surgical techniques and perioperative care, have resulted in a dramatic increase in the recipient and graft survival across all patients. Over the past 3 decades, the solid organ (i.e., liver, lung, kidney, heart) transplantation has become the standard of therapy for millions of patients with end-stage organ failure. However, the side effects of systemically administered immunosuppressive agents are a major barrier to their clinical use and they become a hindrance to long-term success of transplantation.1van Gelder T. van Schaik R.H. Hesselink D.A. Pharmacogenetics and immunosuppressive drugs in solid organ transplantation.Nat Rev Nephrol. 2014; 10: 725-731Crossref PubMed Scopus (66) Google Scholar The development of nanotherapeutics has the potential to overcome this obstacle and it may have a transformative influence on the administration of immunosuppressive agents because the nanoplatform facilitates tailored transport of them to specific solid organs and tissues, diminishing their off-target toxicity to a great extent.2Lin A. Giuliano C.J. Palladino A. et al.Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.Sci Transl Med. 2019; 11Crossref Scopus (266) Google Scholar Over the last decade, immense progress has been made in the use of nanotherapeutics for treating tumors.3Li H. Luo Q. Zhang H. et al.Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation.Chem Soc Rev. 2023; 52: 47-96Crossref Google Scholar,4Tan P. Chen X. Zhang H. et al.Artificial intelligence aids in development of nanomedicines for cancer management.Semin Cancer Biol. 2023; 89: 61-75Crossref Scopus (13) Google Scholar Notably, their success in delivering therapeutic agents to tumors and imaging tumor tissues has raised the confidence of using nanotherapeutics for transplantation.5Cheng C.J. Tietjen G.T. Saucier-Sawyer J.K. et al.A holistic approach to targeting disease with polymeric nanoparticles.Nat Rev Drug Discov. 2015; 14: 239-247Crossref PubMed Scopus (0) Google Scholar,6Shi H.T. Huang Z.H. Xu T.Z. et al.New diagnostic and therapeutic strategies for myocardial infarction via nanomaterials.eBioMedicine. 2022; 78103968Summary Full Text Full Text PDF Scopus (10) Google Scholar The nanotherapeutics have distinct advantages in overcoming the challenges for recipients – increasing the availability of donor organs by preserving their viability, protecting grafts from ischemia reperfusion injury and immune rejection, and preventing post-transplantation tumor recurrence. Inhibitors for mammalian target of rapamycin (mTOR) belong to a family of immunosuppressants with an antitumor efficacy.7Dancey J. mTOR signaling and drug development in cancer.Nat Rev Clin Oncol. 2010; 7: 209-219Crossref PubMed Scopus (328) Google Scholar It has been demonstrated that switching to a mTOR inhibitor-based maintenance regimen soon after transplantation reduces morbidity and death caused by cancer.8Kauffman H.M. Cherikh W.S. Cheng Y. et al.Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies.Transplantation. 2005; 80: 883-889Crossref PubMed Scopus (560) Google Scholar Nevertheless, rapamycin exhibits poor pharmacokinetics, and it is prone to resistance. To address these issues, in a recent issue of eBioMedicine, Yang et al. developed a novel nanotherapeutic strategy by supramolecular assembly of rapamycin into a cytotoxic polymer, 7-ethyl-10-hydroxycamptothecin (SN38), to form prodrug nanoparticles (SRNPs) for simultaneous codelivery of cytotoxic and immunosuppressive agents.9Yang Z.T. Xie H.Y. Wang H.X. et al.A nanotherapeutic strategy that engages cytotoxic and immunosuppressive activities for the treatment of cancer recurrence following organ transplantation.eBioMedicine. 2023; https://doi.org/10.1016/j.ebiom.2023.104594Summary Full Text Full Text PDF Scopus (0) Google Scholar Specifically, Western blot analysis revealed that SN38 had a strong suppressive effect on Akt signaling and the synergistic action of SN38 and rapamycin could prevent activating the Akt/mTOR pathway, offering a hope for overcoming rapamycin resistance. Additionally, cytotoxic SRNPs were systemically assessed in an HCC cell line and an orthotopic HCC mouse model established from C57BL/6 mice. A higher potency of SRNPs in suppressing cell proliferation and inducing cell apoptosis confirmed their remarkable effectiveness in inhibiting tumor growth. Moreover, the treatment with SRNPs significantly decreased the vessel density in tumors, which may be ascribed to the anti-VEGF activity of rapamycin. The immunosuppressive activity of SRNPs was evaluated in an allogeneic rat orthotopic liver transplantation model, which experienced graft loss within two weeks. The results showed that administration of SRNPs substantially alleviated graft damage by inhibiting immunological infiltration and proliferation. Additionally, recipients managed with SRNPs experienced a significantly improved survival rate with preserved liver functions. It is worth noting that an interesting cancer-transplant model simultaneously bearing a tumor xenograft and a skin allograft was employed to evaluate the antitumor and immunosuppressive activity of SRNPs. The experimental data supported a high efficiency of SRNPs in inhibiting tumor growth and reducing the damage to the skin allograft resulting from immune rejection. These findings shed light on the development of nanotherapeutics for solid organ transplantation for prolongation of drug bioavailability, diminishment in drug tolerance as well as reduction in immune rejection. Because of their low toxicity, adaptability, and manipulability, the use of nanotherapeutics could address various barriers for effective transplantation in both graft and recipient therapy. By targeted delivery and regulated distribution of immunosuppressive agents, the nanoplatform has been shown to play a crucial role in performing successful transplants for patients with a high risk of chronic rejection. However, short- and long-term toxicity of nanomaterials for the nanoplatform should be thoroughly assessed, especially their interactions with other biological substances in the human body before they can be applied in clinical settings. Meanwhile, the emergence of ex vivo normothermic machine perfusion (NMP)10Chandak P. Phillips B.L. Bennett D. et al.Modelling acute antibody-mediated rejection of human kidney transplants using ex-vivo warm machine perfusion.eBioMedicine. 2022; 86104365Summary Full Text Full Text PDF Scopus (0) Google Scholar has strengthened the role of the nanoplatform for the therapeutics in protecting grafts. The NMP technique motivates the development of novel delivery approaches for nanotherapeutics, while nanotherapeutics can be directed to targeted grafts during machine perfusion. Nanotherapeutic intervention in conjunction with pretransplant organ preservation via the NMP technique, in vivo nano-imaging for survival assessment of grafts, or optimization of traditional immunosuppressive agent pharmacokinetics could ultimately address the challenges during traditional solid organ transplantation, and they have a great potential in their translation into clinical use. Gang Xu wrote the first draft, and all authors critically evaluated the manuscript. All authors read and approved the manuscript. None declared. This work was supported by the Natural Science Foundation of Sichuan Province (No. 2022NSFSC0843), the China Postdoctoral Science Foundation (No. 2022M712262) and the National Natural Science Foundation of China (No. 52203182, 32271445, and 52073193). A nanotherapeutic strategy that engages cytotoxic and immunosuppressive activities for the treatment of cancer recurrence following organ transplantationThe nanotherapy presented here had enhanced efficacy against tumours and maintained satisfactory immunosuppressive activity and thus has great potential to improve the survival outcomes of patients with a high risk of tumour recurrence following OT. Full-Text PDF Open Access