An Environmentally Responsive Molecular Engineering Framework for Subcellular Drug Translocalization

Abstract The power of drugs lies in their ability to reach their target sites and remain in place for a sufficient duration to exert their therapeutic effects. However, for some drugs, lysosomal phagocytosis presents ongoing challenges. In this study, an engineered o rganelles v isualization d rug‐delivery s ystem (OVDS) is introduced as a subcellular drug visualization and redistribution framework that facilitates the movement of drug molecules from one organelle, specifically lysosomes, to another, such as the mitochondria. As a proof‐of‐concept study, an OVDS is developed to facilitate the translocation of 10‐hydroxycamptothecin (HCPT) from the lysosomes to mitochondria. This modification of subcellular HCPT distribution allows the evasion of lysosome‐mediated HCPT resistance in cancer cells. Unlike traditional chemotherapeutic approaches, when HCPT is incorporated into the OVDS framework (HCPT‐OVDS), the positive charge of the OVDS facilitates protonation, thereby enabling HCPT to escape lysosomes and enter mitochondria. Using HCPT‐OVDS, substantial drug accumulation is achieved at the target sites in HCPT‐resistant cells, with up to 70 ± 6% efficient subcellular translocalization and a 12.8 fold enhancement in cytotoxicity. Overall, the HCPT‐OVDS represents an innovative engineering framework for subcellular spatial redistribution and offers a promising solution for addressing cancer drug resistance.