Spatiotemporally controlled depletion of efflux-dominant cells enhances intratumoral delivery of nanomedicines.

Intratumoral delivery remains a major limitation for nanomedicines in solid tumors, particularly in drug-resistant tumors containing efflux-dominant cellular subpopulations. Using P-glycoprotein (Pgp)-associated resistance as a clinically relevant model of heterogeneous transport barriers, we developed a spatiotemporally controlled strategy to improve nanomedicine delivery through selective depletion of efflux-dominant cells. Pgp-targeted photoimmunotherapy (PIT) selectively eliminated Pgp-overexpressing cells and increased intracellular retention of nanoparticle albumin-bound paclitaxel (nab-paclitaxel), accompanied by ATP redistribution associated with reduced efflux activity. In heterogeneous tumor models, PIT enhanced tumor-level nanoparticle accumulation and improved the antitumor efficacy of nab-paclitaxel compared with monotherapy. In vivo, the combination produced durable tumor suppression without increased systemic toxicity. These findings support the potential of spatiotemporally controlled depletion of efflux-dominant cells to relieve intratumoral transport constraints and enhance nanomedicine delivery.