Liya Sun

Drug-induced pulmonary injury (DIPI) represents a significant, though often under-recognized, complication of pharmacotherapy. With the increasing global use of chemotherapeutic agents, immunomodulators, and novel biologics, the reported incidence of DIPI is rising, thereby posing significant diagnostic and management challenges. This mini-review outlines the mechanisms, clinical manifestations, and current treatment approaches for DIPI, while highlighting recent advances in biomarker discovery and targeted interventions. This review emphasizes early detection and personalized management to mitigate morbidity and mortality associated with this condition.

The overactivation of endosomal Toll-like receptor (TLR) in macrophages plays an important role in the pathogenesis of acute lung injury (ALI). There is currently still a lack of nano-formulated and macrophage-targeted endosomal TLR inhibitors that have been approved for clinical uses. We previously discovered that the elevation of endosomal pH using nanodevices provides a promising strategy to specifically inhibit endosomal TLRs in macrophages. The weakly basic drug hydroxychloroquine (HCQ) has been reported for its capability to accumulate in endolysosomes and modulate the acidity in these compartments. To enhance its macrophage-targeting ability and the therapeutic efficacy in vivo, herein we formulated HCQ into a nanoform using liposomes, named HCQ-L. We found that HCQ-L was less cytotoxic and more effective in inhibiting endosomal TLRs (including TLR3, TLR4, TLR 7/8) than the molecular HCQ. Subsequently, a hexapeptide, Pep12, was inserted onto the surface of HCQ-L to form HCQ-L-P12. Interestingly, Pep12 modification significantly improved the stability of liposomes in aqueous solution for at least 2 years; while having enhanced inhibitory effects on TLR7/8 signaling, HCQ-L-P12 displayed similar effects on inhibiting the TLR4 pathway and down-stream pro-inflammatory cytokine production when compared with HCQ-L. Furthermore, both HCQ nanoformulations potently elevated the endosomal pH. In vivo evaluation showed that HCQ-L-P12 and HCQ-L (but not molecular HCQ) were able to alleviate lung inflammation and injuries by decreasing inflammatory cell infiltration upon intratracheal instillation in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. This research provides a new strategy to fabricate lipid-based nanocarriers for targeted delivery of endosomal pH modulators to treat ALI and other acute and chronic inflammatory disorders.