Virus‐Like Nanotherapeutic for Spatiotemporally Enhancing Antigen Presentation and Cross‐Presentation toward Potential Personalized Immunotherapy

Abstract One of the major causes of immunotherapy resistance is the loss of major histocompatibility complex class I (MHC‐I) molecules in tumor cells or the downregulation of the class I antigen presentation pathway. In this study, a novel virus‐like nanotherapeutic (siRNA@HCM) is developed via encapsulating nanosized siRNA nanoparticles in a hybrid membrane comprising a personalized tumor cell membrane and a universal 293T membrane expressing the mutant vesicular stomatitis virus glycoprotein (mVSV‐G). Upon intravenous administration, siRNA@HCM accumulates at the tumor site and provides two potent driving forces for antitumor immunity. First, mVSV‐G induces the fusion of siRNA@HCM with tumor cell membranes and directly injects siRNAs into the cytoplasm, significantly improving tumor intrinsic MHC‐I antigen presentation. Moreover, mVSV‐G can promote the maturation of dendritic cells, thereby achieving highly efficient antigen cross‐presentation. The results demonstrate that spatiotemporally enhancing tumor intrinsic antigen presentation and cross‐presentation via siRNA@HCM can achieve satisfactory antitumor efficacy and excellent biocompatibility. Immune infiltration analysis shows that siRNA@HCM treatment turns cold tumors into hot tumors. In addition, it significantly promotes the therapeutic effect of programmed death‐1 inhibitor. In summary, virus‐like nanotherapeutics present a promising approach to enhance the antitumor immune response, with distinct advantages for potential personalized therapy and clinical applications.