2. Academic Validation
  3. Triple-Cascade Responsive Pneumatic Nanomotor Enhance Cancer Immunotherapy by Oncolytic Virus-Triggered Pyroptosis

Triple-Cascade Responsive Pneumatic Nanomotor Enhance Cancer Immunotherapy by Oncolytic Virus-Triggered Pyroptosis

  • ACS Nano. 2026 Mar 31;20(12):9784-9801. doi: 10.1021/acsnano.5c19047.
Wen-Da Wang 1 2,  Chi-Hui Yang 3,  Wen-Tao Mo 1 2,  Su-Ran Li 1 2,  Qi-Chao Yang 1 2,  Jun Xie 1 4,  Yun-Hong Zhong 1 4,  Junjie Zhang 1 4,  Cong-Fa Huang 1 2,  Wei-Wei Deng 1 2,  Xian-Zheng Zhang 3,  Zhi-Jun Sun 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China.
  • 2 Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, China.
  • 3 Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430079, China.
  • 4 State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan 430079, China.
PMID: 41842752 DOI: 10.1021/acsnano.5c19047
Abstract

The intravenous delivery of oncolytic viruses (OVs) often demonstrates limited therapeutic efficacy due to rapid clearance by peripheral neutralizing antibodies and poor penetration into deeper tumor regions. To overcome these bottlenecks, we report a triple-cascade responsive pneumatic nanomotor (HLNO) designed for systemic delivery of the oncolytic herpes simplex virus (oHSV). The HLNO nanomotor utilizes a hierarchically structured core-shell design featuring an oHSV core encapsulated within a glutathione-responsive Liposome layer and hyaluronic acid outer shell while incorporating the pH-sensitive nitric oxide (NO) donor. This system enables immune evasion of oHSV in peripheral circulation while demonstrating programmable activation that specifically responds to tumor microenvironment stimuli. It is noteworthy that the HLNO nanomotor utilizes NO-propelled active motion under acidic conditions to enhance extravasation and tissue deep penetration, followed by hyaluronidase-mediated deshielding and glutathione-triggered oHSV release. Then, the HLNO nanomotor activates the Caspase-3/GSDME pathway to induce immunogenic Pyroptosis, which enhances antitumor immunity by increasing CD8+ T cell infiltration and M1-like macrophage polarization while driving vascular normalization and alleviating tumor hypoxia. By integrating immune shielding with cascade-responsive release, this platform addresses key limitations of systemic OVs delivery, offering an approach to enhance immunotherapy efficacy in immunologically "cold" tumors.

Keywords

deep tumor penetration; immune checkpoint blockage; nanomotor; oncolytic virus; pyroptosis.

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