Promotion of NLRP3 autophagosome degradation by PV-K nanodevice for protection against macrophage pyroptosis-mediated lung injury.

Summary

PV-K nanoparticles, intrinsically taken up by macrophages, suppressed NLRP3-mediated pyroptosis and mitigated inflammation in LPS and CLP mouse models of acute lung injury. Mechanistically, PV-K upregulated NRF2, enhanced p62-mediated autophagy, and promoted autolysosomal degradation of NLRP3; the effect was lost with impaired NRF2 signaling.

Key Findings

• PV-K inhibited NLRP3-mediated pyroptosis in mouse bone marrow–derived macrophages and human THP-1–derived macrophages.
• In LPS and CLP mouse models of acute lung injury, PV-K reduced disease severity by alleviating pulmonary inflammation and inhibiting macrophage pyroptosis.
• PV-K upregulated NRF2 signaling, enhanced SQSTM1/p62-mediated autophagy, and promoted autolysosomal degradation of NLRP3; effects were abrogated when NRF2 signaling was impaired.

Clinical Implications

While preclinical, PV-K highlights pyroptosis as a druggable axis in ARDS; future inhaled or targeted delivery could complement lung-protective ventilation by dampening macrophage-driven inflammation.

Limitations

• Preclinical models without human clinical data; safety, biodistribution, and dosing remain untested.
• Nanoparticle formulation and manufacturing scalability for clinical translation are not addressed.

Future Directions

Assess inhaled/targeted delivery, safety and pharmacokinetics, and efficacy in large-animal ARDS models; explore combination with anti-inflammatory agents and ventilatory strategies.