Abstract

Solid tumors frequently develop drug resistance by therapy-induced collagen-dense barriers that impede drug penetration and immune cell infiltration. Here, a traditional Chinese medicine (TCM)-inspired carbon dots (NRG-CDs) system is reported that reprograms cancer cell death from apoptosis to necroptosis, effectively dismantling the collagen barrier typically caused by drug-induced collagen up-regulation while activating immunogenic cell death. By integrating naringenin (NRG) with ε-poly(L-lysine) through dimethyl sulfoxide-assisted solvothermal processing, the resulting NRG-CDs achieve effective cancer cell killing capacity with minimal cytotoxicity toward normal cells. Compared to NRG, the NRG-CDs shift cell death modality from apoptosis to necroptosis, reducing collagen secretion while releasing damage-associated molecular molecules for antigen-presenting cell maturation. Further incorporating oxidized dextran creates an injectable pH-responsive hydrogel (CO-Gel) that can locoregionally release NRG-CDs in the acidic tumor microenvironment. In the aggressive murine 4T1 model, peritumoral CO-Gel administration achieves dual therapeutic outcomes: primary tumor suppression and pulmonary metastasis inhibition. The strategy is further validated in orthotopic hepatic tumors in a rat model, demonstrating broad applicability. This work provides a paradigm shift from conventional cytotoxic drug design to death modality-engineered nanotherapeutics.

文章链接：https://doi.org/10.1002/adfm.202522706