# Pathology-tailored nanotherapy via Galectin-3-targeted and triple-responsive nanoparticles enables multimodal therapy against aortic dissection

## TL;DR

This paper introduces a new nanotherapy targeting Galectin-3 to treat aortic dissection by delivering multiple treatments with high precision to affected cells.

## Contribution

The study introduces a triple-responsive, pathology-tailored nanoplatform for targeted multimodal therapy in aortic dissection.

## Key findings

- The nanoparticles achieved >20-fold aortic accumulation and reduced AD incidence, vascular degeneration, and mortality in vivo.
- In vitro, the nanoparticles enhanced uptake by pathological cell types and reduced inflammatory and degenerative phenotypes.
- The nanoplatform combines on-demand nitric oxide release, Gal-3 blocking, and resveratrol delivery for multi-pathway intervention.

## Abstract

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.

Schematic 1. Schematic illustration of a triple-responsive nanoplatform (MPCR NPs) that enables pathology-tailored targeting via Gal-3 recognition and achieves multimodal therapy for AD. MPCR NPs are constructed from MCP, Prt, and CR through supramolecular co-assembly primarily driven by electrostatic and hydrogen-bonding interactions between MCP and Prt. CMCD modulates the assembly by increasing Prt β-turn conformation, thereby reducing particle size. Upon exposure to pathological stimuli (acidic pH, protease, and H2O2), MPCR NPs undergo cascade release of CR and subsequent RES liberation. The system enables spatiotemporal targeting across ECs, VSMCs, and Mφs during AD progression. Cell-specific therapeutic effects include: (1) on-demand NO therapy for EC restoration and VSMC adaptive remodeling; (2) Gal-3 blocking for inflammation attenuation and contractile phenotype maintenance; and (3) RES-mediated protection of ECs and Mφs, leading to oxidative stress reduction and inflammatory resolution. Collectively, MPCR NPs provide a pathology-adaptive nanotherapeutic strategy with spatiotemporally precise delivery and multi-pathway intervention.

Schematic 1. Schematic illustration of a triple-responsive nanoplatform (MPCR NPs) that enables pathology-tailored targeting via Gal-3 recognition and achieves multimodal therapy for AD. MPCR NPs are constructed from MCP, Prt, and CR through supramolecular co-assembly primarily driven by electrostatic and hydrogen-bonding interactions between MCP and Prt. CMCD modulates the assembly by increasing Prt β-turn conformation, thereby reducing particle size. Upon exposure to pathological stimuli (acidic pH, protease, and H2O2), MPCR NPs undergo cascade release of CR and subsequent RES liberation. The system enables spatiotemporal targeting across ECs, VSMCs, and Mφs during AD progression. Cell-specific therapeutic effects include: (1) on-demand NO therapy for EC restoration and VSMC adaptive remodeling; (2) Gal-3 blocking for inflammation attenuation and contractile phenotype maintenance; and (3) RES-mediated protection of ECs and Mφs, leading to oxidative stress reduction and inflammatory resolution. Collectively, MPCR NPs provide a pathology-adaptive nanotherapeutic strategy with spatiotemporally precise delivery and multi-pathway intervention.

The online version contains supplementary material available at 10.1186/s12951-025-04012-7.