An Environmentally Responsive Molecular Engineering Framework for Subcellular Drug Translocalization

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 organelles visualization drug-delivery system (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.