A Chiral Amino Acid-Modified pH-Responsive Nanoplatform Coactivates Cuproptosis and cGAS-STING Signaling Pathways for Cancer Therapy

We engineered l/d-Cu/Z@MH, a multimodal therapeutic nanoplatform functionalized with hyaluronic acid (HA) and chiral amino acids, to enhance tumor-targeting specificity and cellular internalization. The nanoparticles exhibit pH-responsive degradation, rapidly releasing Cu2+ and MnO2 layers upon cellular uptake. These agents drive a tumor microenvironment (TME)-amplified Fenton-like reaction with endogenous H2O2, generating cytotoxic reactive oxygen species (ROS), depleting glutathione, and augmenting chemodynamic therapy (CDT). Copper ions induce cuproptosis, while manganese ions activate the cGAS-STING signaling pathway. Synergistically, ROS overproduction and cGAS-STING activation provoke endoplasmic reticulum stress and immunogenic cell death (ICD), effectively reprogramming the tumor’s immunosuppressive microenvironment. The results of this study demonstrated potent tumor suppression by l/d-Cu/Z@MH nanoparticles, with l-Cu/Z@MH showing superior efficacy.