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

## TL;DR

A new stealth nanomedicine extends pain relief after surgery by inhibiting inflammation and using mild heat triggered by light.

## Contribution

This work introduces a novel stealth nanomedicine that inhibits complement-mediated inflammation and enables on-demand thermo-responsive pain management.

## Key findings

- LMIBP evades immune clearance by suppressing complement C3 activation and promoting anti-inflammatory macrophage polarization.
- Mild NIR light triggers localized heat and drug release without tissue damage or inflammation.
- LMIBP provides prolonged analgesia with on-demand reactivation in a preclinical incision model.

## Abstract

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.

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