A unified biochemical-physical regulatory nanoparticle modulates tumor mechanics to augment nanomedicine penetration and antitumor efficacy.

The abnormal mechanical microenvironment in solid tumors is a self-reinforcing alliance between activated cancer-associated fibroblasts (CAFs) and dense extracellular matrix (ECM), forming an impenetrable barrier that shuts out nanomedicines. Biochemical approaches suppress CAFs but poorly penetrate stroma or relieve matrix barriers, whereas physical methods loosen ECM transiently but lack specificity and sustained CAFs inhibition. Here we report a responsive drug conjugate (PFD-TK-Cy) that self-assembles into nanoparticles (PFD-TK-Cy NPs) for integrated biochemical CAFs inhibition and physical ECM relaxation. Upon specific uptake by CAFs, elevated intracellular reactive oxygen species (ROS) trigger cleavage of the thioketal linker in PFD-TK-Cy, releasing modified pirfenidone (PFD-OH) to suppress pro-fibrotic signaling and a cyanine-based photosensitizer (SO3Cy) to generate localized mild hyperthermia (ca. 43 °C) for softening the matrix. This spatiotemporally coordinated strategy disrupts the vicious loop between CAFs and ECM, leading to reduced solid stress, improved blood perfusion, and enhanced intratumoral delivery of Doxil in stroma-rich orthotopic breast cancers. This study offers a promising nanoplatform for overcoming mechanical barriers in solid tumors.