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

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. 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. 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.