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<p>Living cell-derived bioactive nanotherapeutics have advanced the development of highly effective cancer treatment strategies. In this study, we elaborately develop a multifunctional nanointegrator (DOX@DPNVs) from bioengineered nanovesicles (NVs) that act as a potent immunoactivator to overcome immunosuppression for enhanced tumor therapy. By genetically modifying tumor cells with PD-L1 knockout as well as PD-1 overexpression, these cells were subsequently treated with immunogenic cell death (ICD)-inducer (i.e., doxorubicin (DOX)) to trigger the release of damage-associated molecular patterns (DAMPs) in the extracellular environment. The resultant cell-involved mixture undergoes a one-step sonication and extrusion process, resulting in the formation of DOX@DPNVs, which are co-loaded with DAMPs and DOX and display PD-1 molecules on their surface. Consequently, the bioactive DOX@DPNVs enable the delivered DAMPs to combine with the DOX-induced ICD effect to accelerate DAMPs-mediated immune activation and effectively blockage the PD-1/PD-L1 axis for restoring cytotoxic function of T cells, eliciting an robust anti-tumor response in an aggressive squamous cell carcinoma mouse model. This naturally occurring NVs-based dual-throttle strategy provides an effective immunoactivation strategy to overcome immunosuppressive tumor environment, offering a promising platform for combating aggressive cancers.</p> Graphical Abstract <p></p>

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A biomimetic nanointegrator synergizing “dual-throttle” immune checkpoint blockade and enhanced DAMPs-mediated immune activation for potent anti-tumor T‑cell immunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月14日

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  • Han-Zhe Liu,
  • Pan Liu,
  • Zi-Yi Chen,
  • Tong Wang,
  • Lan Liu,
  • Qiu-Jing Li,
  • Zheng-Jun Shang,
  • Guo-Feng Luo

摘要

Living cell-derived bioactive nanotherapeutics have advanced the development of highly effective cancer treatment strategies. In this study, we elaborately develop a multifunctional nanointegrator (DOX@DPNVs) from bioengineered nanovesicles (NVs) that act as a potent immunoactivator to overcome immunosuppression for enhanced tumor therapy. By genetically modifying tumor cells with PD-L1 knockout as well as PD-1 overexpression, these cells were subsequently treated with immunogenic cell death (ICD)-inducer (i.e., doxorubicin (DOX)) to trigger the release of damage-associated molecular patterns (DAMPs) in the extracellular environment. The resultant cell-involved mixture undergoes a one-step sonication and extrusion process, resulting in the formation of DOX@DPNVs, which are co-loaded with DAMPs and DOX and display PD-1 molecules on their surface. Consequently, the bioactive DOX@DPNVs enable the delivered DAMPs to combine with the DOX-induced ICD effect to accelerate DAMPs-mediated immune activation and effectively blockage the PD-1/PD-L1 axis for restoring cytotoxic function of T cells, eliciting an robust anti-tumor response in an aggressive squamous cell carcinoma mouse model. This naturally occurring NVs-based dual-throttle strategy provides an effective immunoactivation strategy to overcome immunosuppressive tumor environment, offering a promising platform for combating aggressive cancers.

Graphical Abstract