Reprogramming Tumor Cell Death via Processing Natural Drug to Carbon Dots Overcomes Collagen Barrier and Activates Antitumor Immunity

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.