Pirfenidone encapsulated in succinylated gelatin-coated liposomes exhibits sustained antifibrotic effects in vitro models of renal, pulmonary, and hepatic fibrosis.

Fibrosis is characterized by excessive extracellular matrix accumulation, leading to organ dysfunction and irreversible damage in advanced stages. Challenges in sustaining drug levels within fibrotic lesions with the currently used antifibrotic therapies, including pirfenidone, often necessitate high drug doses that can cause systemic side effects. Here, we introduce a succinylated gelatin (SG)-coated liposome (SG-lip) system, which enhances pirfenidone retention and enables enzyme-responsive release at sites of fibrosis in an in vitro model. The SG coating, which ensures high collagen-binding affinity, is degraded by matrix metalloproteinases, which are overexpressed in fibrotic tissues, allowing targeted drug release. In vitro experiments using NRK-49F (kidney fibroblasts), WI-38 (lung fibroblasts), and RI-T (hepatic stellate cells) cultured on collagen I gel, SG-lip prolongs drug retention and sustains localized release at sites of fibrosis. In experiments simulating transient drug exposure by washing away the residual pirfenidone after treatment, pirfenidone-loaded SG-lip significantly inhibit fibroblast proliferation, invasion, and myofibroblast differentiation. Our enzyme-triggered drug delivery system enhances the antifibrotic efficacy of pirfenidone, with the potential to reduce systemic exposure and associated side effects. These findings highlight SG-lip as a promising platform for targeted antifibrotic therapy, offering a novel strategy to improve treatment of fibrosis.