mTORC1 Selective Nano‐Inhibitor by Disrupting the Lysosomal Arginine‐SLC38A9‐ mTORC1‐CDKs Axis for Precision Bladder Cancer Therapy

Abstract

Abstract The absence of precise targeting and defined mechanisms, akin to small molecules, remains a major barrier to the clinical translation of nanomedicines. Mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cell proliferation and metabolism, is linked to abnormal activation in various diseases like cancers. While small‐molecule inhibitors of mTORC1 are limited, they remain a focus. Here, a strategy is presented for mTORC1‐specific nano‐inhibitors targeting the lysosomal arginine (Arg)‐SLC38A9‐mTORC1 pathway. Using [2Fe‐2S]CO 6 as a universal paradigm, nanomedicines are developed (e.g., ZnPc‐SFeCO) that degrade Arg in the lysosome, inhibiting SLC38A9 activation and blocking mTORC1 recruitment. ZnPc‐SFeCO inhibits mTORC1 at ultra‐low concentrations (1.07 ng mL −1 ), with three orders of magnitude greater specificity than the clinical small molecule rapamycin. SLC38A9 knockout abolishes nanomedicine efficacy. Differential responses to the inhibitors are also observed in normal and bladder cancer cells, linked to SLC38A9 expression levels, suggesting potential for precise treatment of non‐muscle invasive bladder cancer (NMIBC). In vivo, ZnPc‐SFeCO combined with photodynamic therapy outperformed MMC in preventing tumor recurrence and extending survival. This work establishes a promising approach for developing mTORC1‐specific nano‐inhibitors with well‐defined targets and mechanisms, offering new insights into the development of precision nanomedicines for cancer therapy.