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Background <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月4日

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  • He Wang,
  • Yang Yu,
  • Wenbin Zhou,
  • Baihui Miao,
  • Yanqing Zhang,
  • Jiahao Zhu,
  • Ziyi Lin,
  • Jiayang Han,
  • Xiaoding Xu,
  • Fenghe Zhang,
  • Qing Li

摘要

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.

Graphical Abstract