Nanochirality-programmed type-I photosensitizer enables deep-tumor photodynamic therapy by reducing...

Tumor hypoxia and poor penetration of therapeutics across tumor-microenvironment barriers remain major obstacles to effective cancer therapy, including photodynamic therapy (PDT). Here we introduce a nanochirality-programmed assembly (L-Chi-GAIN) in which nanochirality drives site-selective assembly that activates Type-I reactive oxygen species (ROS) generation with significantly reduced oxygen dependence and diminishes hyaluronan-mediated matrix adhesion, thereby enabling deep intratumoral therapy. Glycosylation imparts structural chirality to graphene quantum dots (GQDs), directing site-selective assembly of indocyanine green (ICG) that turns on photoinduced electron transfer (PET), producing a 64-fold increase in ROS relative to free ICG. Nanochirality also modulates assembly-extracellular matrix (ECM) interactions. L-GQDs show a less favorable hyaluronan binding free energy (ΔG_bind), thereby accelerating interstitial transport and resulting in ∼3-fold greater penetration depth and ∼ 21-fold higher mean intratumoral ICG signal within the penetrating area relative to liposomal carriers. Under near-infrared irradiation, L-Chi-GAIN elicits strong oxidative stress and triggers Gasdermin-D (GSDMD)-dependent pyroptosis, leading to significant suppression of tumor growth. This work offers a nanochirality-guided design strategy for PDT in deep tumors by coupling site-selective assembly with stereoselective navigation of the ECM.