Glycosylated Multifunctional Nanoplatform Co-Delivering Artemisinin: Synergizing NIR-Responsive Phototherapy with Chemodynamic Therapy for Precision-Targeted Tumor Theranostics.

Phototherapy is promising because of its spatiotemporal precision, minimal invasiveness, and low systemic toxicity, but most antitumor delivery systems rely on EPR-mediated passive targeting and nonspecific uptake, resulting in suboptimal tumor drug accumulation and reduced efficacy. We innovatively developed a lactose-modified, self-assembled, and NIR-responsive type-I photosensitizer, BDPL, with precise HepG2-targeting ability. Multiglycosylation enables the efficient generation of O2 -• via the regulation of carbohydrate‒carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates, enabling BDPLs to be used for NIR-responsive type I photodynamic therapy (PDT) and photothermal therapy (PTT). Concurrently, to address the inherent limitations of conventional phototherapy, specifically inadequate tissue penetration and profound tumor hypoxia, we engineered ABDPL@Fe NPs through the strategic loading of hydrophobic artemisinin (ARTE) with amphoteric BDPL followed by Fe(III) coordination, establishing a synergistic therapeutic platform for increased tumor suppression. This innovative nanoplatform serves as a nanogenerator of carbon-centered and hydroxyl radicals under hypoxic and light-deprived conditions, revealing significant potential for treating deep-seated tumors with hypoxic microenvironments. For the first time, we report a glycosylated NIR-activated nanoplatform that unleashes a ROS storm to disrupt tumor antioxidant defenses, inducing synergistic apoptosis-ferroptosis death. This strategy has antitumor efficacy and improves precision-targeted treatment.