Dual-loaded homotypic exosomes with endogenous IR808 and pH-responsive DOX drive sequenced chemo-PDT and convert “cold” OSCC tumors “hot”

BACKGROUND: Chemotherapy remains central to oral squamous cell carcinoma (OSCC) management but is constrained by poor specificity, systemic toxicity, multidrug resistance, and limited durability. Tumor-derived exosomes (TEX) offer a clinically relevant carrier owing to their biocompatibility, low immunogenicity, and homotypic targeting; however, prevailing high-efficiency loading methods (electroporation/sonication/extrusion, etc.) may disrupt membrane proteins, promote cargo leakage and aggregation, and increase costs-hindering clinical translation. RESULTS: Here we report IR808/Doxorubicin@Tumor-derived Exosomes (ID-TEX) that combine endogenous IR808 loading (preserving membrane integrity and homotypic ligands) at cell level with covalent, pH-responsive anchoring of doxorubicin via a hydrazone linker on the exosome surface (HYD-DOX). Upon cellular uptake, acidification in endosomes/lysosomes rapidly cleaves the linker, releasing DOX to induce nuclear DNA damage, followed by IR808-mediated photodynamic therapy (PDT) to amplify oxidative stress-establishing a sequenced chemo-PDT cascade. Leveraging the native integrin repertoire and CD47 signaling of TEX, ID-TEX achieves active homing, prolonged circulation, uniform intratumoral distribution, and deep penetration. Mechanistically, the intensified oxidative and multi-pathway cytotoxic stress elicits immunogenic cell death (ICD), promotes dendritic cell maturation, and recruits CD8⁺ and CD4⁺ T cells, converting "cold" OSCC into "hot" tumors and transforming localized photochemotherapy into systemic antitumor immunity. CONCLUSIONS: Centering this chemo-photodynamic-immunotherapeutic cascade on enhanced ROS, ID-TEX concurrently improves efficacy, reduces toxicity, and strengthens immune modulation, underscoring strong translational potential for precision OSCC therapy.