Nanomotors with Dual Targeting and Self-Feedback Degradation Performance for the Treatment of Sepsis

Activated neutrophils and dysregulated inflammatory infiltration are pivotal factors in the pathogenesis of sepsis; however, precise targeting strategies and sensitive drug release triggers remain lacking. Herein, we propose a novel dual-targeting strategy that integrates inflammatory microenvironment recognition with molecular recognition, and establish a self-feedback drug release mechanism. Specifically, a NOR/NOD@Lip/DOX/BSA (abbreviated as NO(R/D)@Lip/DOX/B) nanomotor was constructed, comprising an inflammatory targeting module (nitric oxide release lipids, NOR), a self-feedback/degradation module (nitric oxide -responsive degradable lipids, NOD), a molecular recognition module (bovine serum albumin, BSA), and the loaded drug doxorubicin (DOX). These nanomotors achieve chemotaxis toward activated neutrophils expressing inducible nitric oxide synthase (iNOS) in the inflammatory microenvironment via the inflammatory targeting module during blood circulation. Subsequently, BSA-based molecular recognition module enables precise targeting of Fc-Gamma (Fc-γ) receptors overexpressed on activated neutrophils. As NO accumulates, the NOD structure within the degradation module gradually breaks down, triggering the release of DOX to specifically eliminate activated neutrophils. In lipopolysaccharide-induced sepsis model, the nanomotor reduced serum inflammatory cytokines and ameliorated multi-organ damage. This dual targeted and self-feedback degradation technology based on NO release and albumin modification for nanomotors provides a new approach for precise in vivo drug delivery for the treatment of inflammatory diseases.