STAR Therapy: Spatiotemporal Antitumor Regimen via a Size‐Gated DNA Hydrogel Drug Delivery System

ABSTRACT Current cancer therapies for solid tumors are significantly hampered by the dense tumor extracellular matrix (ECM), which restricts antitumor drug penetration and accumulation. Hence, there is a critical need for controllable drug delivery systems capable of spatiotemporally controlling the sequential action of ECM‐modulating agents and cytotoxic drugs. However, conventional carriers often suffer from “non‐selective synchronous release”, failing to achieve such spatiotemporal control. Herein, we propose a spatiotemporal antitumor regimen (STAR) based on a size‐gated DNA supramolecular hydrogel (DSH) drug delivery system. In this system, a small‐molecule drug Losartan (Los) and a larger indocyanine green‐loaded platelet‐mimetic particle (ICG/PLT) are co‐encapsulated within the DSH. The programmable size‐selectivity of DSH allows for the rapid diffusion of Los to first remodel tumor ECM by reducing matrix density and enhancing tissue perfusion; meanwhile, the larger ICG/PLT particles are retained within the hydrogel structure and released later along with hydrogel degradation. Notably, this size‐gated sequential release strategy significantly enhances the accumulation of ICG/PLT at the tumor site, resulting in superior light‐activated photodynamic therapeutic outcomes against tumors. Taken together, this study establishes a novel STAR paradigm based on size‐gated DSH, holding promise to advance the therapeutic strategy for solid tumors with dense ECM.