Prodrug-Engineered PI3K/mTOR Nanoblockers Enable Coordinated Tumor Control and Allograft Protection after Transplantation

Abstract Organ transplant recipients with malignancies require therapeutic strategies that control tumor progression without compromising allograft protection. Although mTOR inhibition provides a clinically validated strategy for balancing immunosuppression and tumor control after transplantation, compensatory PI3K/Akt activation limits durable efficacy. Dual PI3K/mTOR blockade represents a rational solution, yet its therapeutic potential is restricted by suboptimal pharmacological properties, including insufficient tissue exposure and dose-limiting toxicity, which compromise sustained target engagement. Here, we developed a prodrug-enabled nanoliposomal platform (PMIProsome) for sustained dual PI3K/mTOR inhibition by converting PF-04691502, a representative dual PI3K/mTOR inhibitor, into a disulfide-linked cholesterol prodrug. PMIProsome optimized systemic drug exposure by enhancing tumor accumulation and reducing systemic toxicity, enabling sustained PI3K/Akt/mTOR pathway inhibition and durable tumor control in an orthotopic hepatocellular carcinoma model. Beyond tumor suppression, PMIProsome retained immunomodulatory activity by attenuating cytotoxic T-cell activation and inflammatory responses, thereby promoting allograft survival. In a concomitant tumor-allograft model, PMIProsome achieved simultaneous tumor control and allograft protection, overcoming the therapeutic conflict between antitumor efficacy and immunosuppression after transplantation. Collectively, these findings establish prodrug-engineered PI3K/mTOR nanoblockers as a therapeutic strategy for coordinating tumor control and allograft protection after transplantation.