Dual-targeted and ROS-responsive dexamethasone prodrug liposomes for enhanced therapy of acute lung injury

The clinical application of dexamethasone (DEX) in acute lung injury (ALI) is constrained by systemic toxicity, poor localization to inflamed sites, and limited lipophilicity that hampers nano-encapsulation. To overcome these barriers, we engineered a novel DEX prodrug liposome that couples high encapsulation efficiency, active biological targeting with disease-triggered release. Inspired by the drug-loading paradigm of Onivyde®, we installed a weak-base handle (4-piperidinopiperidine) on DEX to generate a prodrug (DPD) to achieve efficient active loading into liposomes (LipDPD; encapsulation efficiency > 96%). Meanwhile, we incorporated an ROS-labile thioether linker in this prodrug to ensure spatially controlled activation of the parent drug within the ROS-rich inflammatory lung microenvironment while limiting off-target exposure. Besides, the liposomes were further decorated with Sialic Acid (SA) to yield SA@LipDPD, configured to engage L-selectin on circulating neutrophils and E-selectin on activated endothelium. This dual-targeting strategy produced a more than 2-fold increase in pulmonary accumulation of nanocarriers within 2 h in inflamed murine lungs. In LPS-induced ALI, SA@LipDPD significantly suppressed pro-inflammatory cytokines (TNF-α reduced by > 3-fold; IL-6 by > 10-fold), curtailed neutrophil infiltration by > 5-fold, and preserved alveolar-capillary barrier integrity. Collectively, these results position SA@LipDPD as a targeted corticosteroid platform that concentrates anti-inflammatory activity where needed while limiting off-target effects, offering a promising therapeutic avenue for ALI and other inflammatory diseases.