Design of a bispecific peptide-nanozyme conjugate for cancer immunotherapy.

Abstract

Despite advances in cancer immunotherapy, clinical efficacy remains constrained by immunosuppressive tumor microenvironment (TME), including PD-L1-mediated T cell dysfunction and CXCL8-driven myeloid cell recruitment. To address this, a bispecific peptide-nanozyme conjugate (BsPNEC) is engineered. Leveraging iterative structure-guided optimization, we first develop q6w, a proteolysis-resistant D-peptide targeting CXCR1/2, and conjugate it to a PD-L1-blocking peptide to generate a bispecific peptide qGA. To augment the therapeutic efficacy, qGA is conjugated to Fe₃O₄ nanozymes with peroxidase-mimetic activity. The Fe₃O₄ nanozymes catalytically decompose H₂O₂ into reactive oxygen species (ROS), thus activating the cGAS-STING pathway to potentiate CD8⁺ T cell infiltration and activation in anti-PD-1-resistant tumor model. The BsPNEC platform integrates tumor-targeted delivery, magnetic resonance imaging (MRI) contrast capabilities, and robust inhibition of tumor growth. Our findings present a synergistic immunotherapeutic strategy that simultaneously skews immunosuppressive TME and amplifies T cell immune response.