Solid tumors often develop drug resistance by obstructing drug penetration and immune cell infiltration through treatment-induced dense collagen barriers. Here, a traditional Chinese medicine-inspired carbon dot (NRG-CDs) system is reported, which reprograms cancer cell death from apoptosis to necroptosis, effectively eliminating the collagen barriers typically caused by drug-induced collagen upregulation while activating immunogenic cell death. By integrating naringenin (NRG) with ε-poly(L-lysine) through dimethyl sulfoxide-assisted solvothermal treatment, the resulting NRG-CDs achieve effective cancer cell killing while minimizing cytotoxicity to normal cells.Compared to NRG, NRG-CD shifts the mode of cell death from apoptosis to necroptosis, reduces collagen secretion, and simultaneously releases damage-associated molecular molecules to promote the maturation of antigen-presenting cells. Further incorporation of oxidized dextran can produce an injectable pH-responsive hydrogel (CO-Gel) that allows local release of NRG-CD in the acidic tumor microenvironment. In an aggressive mouse 4T1 model, peritumoral administration of CO-Gel achieved dual therapeutic outcomes: inhibition of primary tumors and suppression of lung metastasis. This strategy was further validated in an orthotopic liver tumor model in rats, demonstrating broad applicability. This work provides a paradigm shift from traditional cytotoxic drug design to the engineering of nanomedicines based on cell death modalities.

Innovation Points

Innovative integration of traditional Chinese and Western medicine treatment concepts: This study is the first to integrate the active component of traditional Chinese medicine herbs (nobiletin) with modern nanomaterials (carbon dots) at the molecular level, creating a new therapeutic system that combines the multi-target characteristics of natural drugs with the efficient delivery advantages of nanomaterials. This provides a novel technical pathway for the modernization and application of traditional medicine. This integration is not a simple combination; rather, the chemical synthesis achieves structural reorganization and functional synergy of the components, giving the final product new biological effects that surpass those of individual components.

Original link

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

Advanced Functional Materials ( IF 19 )

Pub Date : 2025-11-10

DOI: 10.1002/adfm.202522706

Zekun Yan,  Hongwei Cheng,  Yupeng Liu,  Wenfeng Xu,  Quansheng Cheng,  Lingyun Li,  Xue Wu,  Yingqi Liang,  Jing Zhao,  Gang Liu,  Shaoping Li,  Songnan Qu