Artesunate-mycophenolate Mofetil Dimer Micelles Alleviate Allogeneic Skin Graft Rejection by Inhibiting the TLR-4 Pathway in Macrophages.

Background: Organ transplantation continues to be an essential therapeutic option for patients afflicted with end-stage organ failure. However, long-term administration of immunosuppressive agents has the potential to trigger severe adverse effects, including concurrent myelosuppression and systemic toxicity. Targeted delivery of small molecule compounds to immune organs, combined with chemical modification, may well offer a solution to these unmet needs. Methods: Overall, we carried out molecular editing on artesunate (ART) and mycophenolate mofetil (MMF). These compounds were then further optimized through PEGylation using amphiphilic polymers. The PEGylated ART-MMF nano-prodrugs (AMNPs) is capable of self-assembling to generate immunosuppressant nanoparticles, enabling targeted therapeutic delivery to immune organs. In addition, leveraging the allogeneic skin transplantation mouse model empowers us to comprehensively assess the immunotherapeutic efficacy of AMNPs. Results: AMNPs exhibit a more potent immunosuppressive effect and enhanced biocompatibility. In vivo, AMNPs more effectively suppressed the expression of Tumour Necrosis Factor-α (TNF-α) and interleukin 6 (IL-6) in macrophages and proliferation of CD45.1⁺ C57BL/6 mice T cells in CD45.2⁺ C57BL/6 mice. In vitro, AMNPs effectively inhibited the expression of histocompatibility complex II (MHC-II) on Lipopolysaccharide (LPS) induced macrophages and further promoted the expression of CD206 on macrophages induced by tumor supernatants. After depleting macrophages in C57BL/6 mice, the significant effect of AMNPs on T cell anti-inflammatory differentiation was abolished. Conclusion: These findings suggest that targeted delivery of AMNPs using a prodrug-assembled nanoparticles may provide a therapeutic option for combating organ rejection.