Spatiotemporally cascade-driven "Lipo" enhance extracellular matrix penetration and remodel intercellular crosstalk in pulmonary fibrosis.

Pulmonary fibrosis (PF) is an inevitable phase of many respiratory diseases with high mortality and limited effective treatments in the clinic. In PF, aberrant extracellular matrix (ECM) deposition is a significant pathological structural alteration that blocks intercellular crosstalk and hinders the deep penetration of therapeutics into lung tissues, reducing the effectiveness of conventional treatment strategies. Herein, a penetrating enhancer (Lipo) composed of thermosensitive liposome shells loaded with collagenase IV and micellar cores containing thioketal bonds encapsulated with curcumin and decorated with cyclic RGDfc, is developed to alleviate PF. Specifically, Lipo exhibit a cascade-responsive pattern to achieve precision delivery of curcumin through thermosensitivity, enhanced ECM penetration, site-specific targeting, and rapid release in injured alveolar epithelial type II cells (Cell). Subsequently, intercellular crosstalk is remodeled through the curcumin-mediated repair of Cell, combined with collagenase IV-mediated ECM degradation to inhibit myofibroblasts, ultimately achieving PF reversal. This work provides an innovative approach to enhance ECM penetration of therapeutics before remodeling intercellular crosstalk, addressing multi-phase PF therapy.