Biometallic peptide-drug conjugates in photo-crosslinkable hydrogels enable combined photothermal-chemotherapy against breast cancer

Peptide-drug conjugates (PDCs) offer a powerful therapeutic modality by integrating the targeting specificity of peptides with the cytotoxic efficacy of chemotherapeutics, thereby improving antitumor performance while reducing off-target toxicity. In this study, we engineered biometallic PDCs composed of peptide nanofibers (PNFs), gold nanoparticles (GNPs), and doxorubicin (DOX), termed PGDCs, and incorporated them into photo-responsive dual-network hyaluronic acid hydrogels for combined photothermal and chemotherapeutic (PTT/CT) treatment of breast cancer. The hydrogel was formed by mixing oxidized methacrylated hyaluronic acid (O-HAMA) with PGDCs, followed by rapid photo-crosslinking under 365 nm UV light, achieving gelation within 90 s for localized, on-demand drug deployment. The resulting O-HAMA/PGDC hydrogels exhibited pH-responsive drug release under tumor microenvironments and robust photothermal performance under NIR irradiation. In vitro and in vivo evaluations revealed strong tumor suppression, with 98% inhibition efficiency, effective tumor ablation, and minimal damage to surrounding healthy tissues. The structural modularity of PGDCs-allowing simultaneous integration of metals, peptides, and drugs-opens pathways for designing highly effective, tumor-selective nanotherapeutics with controlled activation, efficient internalization, and combined therapeutic outcomes.