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

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.