Reshaping the cardiac microenvironment: a colchicine-loaded nanoplatform with lesion targeting and matrix penetration for myocardial fibrosis therapy.

Myocardial fibrosis (MF), a major driver of cardiovascular disease progression, is characterized by persistent inflammation, aberrant activation of cardiac fibroblasts, and excessive extracellular matrix (ECM) deposition. Current therapeutic strategies are constrained by limited efficacy, safety concerns, and insufficient drug accumulation and distribution within fibrotic lesions due to dense ECM barriers. Herein, we developed a lesion-targeting and ECM-penetrating nanoplatform (TIMP/Col@HH) by modifying a flexible HSA-HAase (HH) nanocapsule with a tissue inhibitor of metalloproteinases (TIMP) peptide, followed by colchicine (Col) loading. In this system, the TIMP peptide promotes accumulation in fibrotic myocardium through recognition of MMP2 overexpressed in fibrotic lesions, while the HH nanocapsule facilitates intralesional distribution within the fibrotic matrix, thereby improving local delivery of colchicine. The resulting nanoparticles exhibited favorable biocompatibility, enhanced cardiac accumulation, and improved distribution in fibrotic myocardial tissue. In vitro, TIMP/Col@HH suppressed pro-inflammatory macrophage activation, inhibited cardiac fibroblast activation and collagen deposition, and interrupted inflammation-driven fibrosis in a coculture model. In an isoproterenol-induced MF mouse model, TIMP/Col@HH exerted pronounced anti-inflammatory and anti-fibrotic effects and significantly improved cardiac function. Collectively, TIMP/Col@HH represents a promising nanotherapeutic strategy for myocardial fibrosis by integrating lesion targeting, enhanced matrix penetration, and colchicine-based intervention.