DePEGylated liposomes incorporating novel amino acid lipids enable effective inhalation of asiatic acid for idiopathic pulmonary fibrosis treatment

Inhalable liposomes modified with polyethylene glycol (PEG) serve as effective carriers for pulmonary drug delivery. However, the significantly lower protein concentration in the pulmonary microenvironment compared to plasma disrupts the exchange between protein and PEG-lipid, resulting in high retention of PEG which impedes cellular uptake. Furthermore, accelerated blood clearance mediated by anti-PEG IgM antibodies diminishes therapeutic outcomes and increases adverse reactions. To address these issues, we developed a novel strategy to construct inhalable dePEGylated liposomes using amino acid lipids (ALs) that were composed of anionic head groups, L-aspartic acid or L-glutamic acid linker and double alkyl chains. The dePEGylated liposomes are utilized to facilitate pulmonary delivery of asiatic acid (AA) for the treatment of idiopathic pulmonary fibrosis (IPF). Compared to PEGylated liposomes, dePEGylated liposomes exhibited promoted cellular uptake and transcellular transport by lung epithelial cells, effectively evaded clearance by alveolar macrophages, and enhanced pulmonary drug exposure, leading to improved therapeutic efficacy against IPF in mice. Our findings highlight the novel ALs-incorporated dePEGylated liposomes as a promising strategy to enhance treatment efficacy for IPF and overcome the limitations of PEGylated liposomes, which offers an efficient pulmonary drug delivery strategy for the other pulmonary diseases as well.