Lysosome-Mitochondria\nCascade Targeting Nanoparticle\nDrives Robust Pyroptosis for Cancer Immunotherapy

The subcellular distribution of cargoes plays a crucial\nrole in\ndetermining cell fate and therapeutic efficacy. However, achieving\nthe precise delivery of therapeutics to specific intracellular targets\nremains a significant challenge. Here, we present a trimodular and\nacid/enzyme-gated nanoplatform (TAEN) that undergoes disassembly within\nacidic endosomes and then is cleaved by lysosomal cathepsin B to facilitate\nefficient and targeted transport of released cargoes into mitochondria\ncompartments. By utilizing this nanovehicle, we successfully achieve\nselective sorting of photosensitizer molecules into mitochondria with\na colocalization coefficient of up to 0.98, leading to the generation\nof reactive oxygen species stress specifically within the mitochondria\nfor potent pyroptosis-based cancer therapy. The induction of mitochondrial\nstress triggers the intrinsic apoptotic pathway as well as caspase-3/gasdermin-E\n(GSDME) cascade, resulting in an enhanced cancer cell killing efficacy\nby nearly 2 orders of magnitude as compared to lysosomal stress. Furthermore,\ndue to its superior capability to stimulate both innate and adaptive\nimmune responses, our mitochondria-sorted nanophotosensitizer exhibits\nrobust antitumor immune efficacy in multiple tumor-bearing mice models.\nThis study not only provides insights into engineering nanomedicines\nfor subcellular targeted delivery but also offers a valuable toolkit\nfor advanced research in the field of nanobiology at subcellular resolution.