Complement-inflammation inhibition via stealth nanomedicine for mild thermo-responsive postoperative on-demand pain management.

Complement- and inflammation-cascade activation-induced clearance of nanomedicines severely limits their efficacy in postoperative pain management. Here, we report a stealth nanomedicine (LMIBP) designed to directly address this challenge, enabling mild, on-demand, thermoresponsive pain relief via inhibition of complement-mediated inflammation. LMIBP integrates ginsenoside Rg3-modified stealth liposomes with dendritic mesoporous silica nanoparticles (DMSNs) loaded with indocyanine green (ICG), perfluoropentane (PFP), and levobupivacaine. Rg3 replaces PEG and cholesterol to suppress complement C3 activation, reduce pro-inflammatory cytokine production, and promote M2 macrophage polarization, thereby extending in vivo retention time by evading immune clearance. Under mild Near-infrared (NIR) light irradiation, ICG generates localized heat with a moderate thermal effect to avoid tissue damage and trigger PFP's liquid-to-gas phase transition, thereby forming microbubbles for ultrasound imaging guidance and accelerating levobupivacaine release. In the preclinical incision pain model, LMIBP prolongs analgesia and enables on-demand reactivation with repeated NIR without neurotoxicity or inflammation. This work pioneers complement-inflammation inhibition as a core design principle for stealth nanomedicines, providing a clinically translatable strategy for ultrasound-guided, mild thermo-responsive on-demand postoperative pain management.