Pathology-tailored nanotherapy via Galectin-3-targeted and triple-responsive nanoparticles enables multimodal therapy...

Aortic dissection (AD) is a life‑threatening vascular disorder with high mortality and no effective pharmacological treatment. Addressing its multicellular and dynamic pathology requires strategies that precisely modulate inflammatory and degenerative processes, yet existing targeted delivery approaches lack the spatiotemporal and cellular precision required. Here, we establish Galectin‑3 (Gal‑3) as a therapeutic delivery target for cardiovascular nanomedicine and introduce a modular, pathology‑tailored nanoplatform synergizing nitric oxide (NO) therapy with multi‑pathway intervention. Gal‑3 is persistently expressed on inflamed endothelial cells, macrophages, and smooth muscle cells during AD progression, providing a tractable target for lesion‑specific engagement. The nanoparticles, created from a previously unexplored integration of a Gal‑3‑binding polysaccharide, a nitric oxide-generating peptide, and a hydrophobic drug carrier, uniquely combine triple responsiveness to pH, protease, and oxidative stress with on‑demand NO release and controlled resveratrol co‑delivery. In vitro, they enhanced uptake across pathological cell types and attenuated inflammatory and degenerative phenotypes. In vivo, they achieved early lesion targeting, > 20‑fold aortic accumulation, and marked reductions in AD incidence, vascular degeneration, and mortality. This work establishes Gal‑3‑targeted nanotherapy as a broadly applicable paradigm for pathology‑adaptive intervention in AD and one that may be adapted for broader cardiovascular applications.