Intelligent hyaluronidase-responsive supramolecular nanoassemblies for programmable dual-drug delivery and NIR-II photothermal therapy of atherosclerosis

The development of controllable nanoplatforms with disease-specific responsiveness and programmable therapeutic functions is vital for treating complex cardiovascular diseases such as atherosclerosis. Herein, we present an intelligent, next-generation nanoplatform (HALA@Ag₂S) that integrates enzyme-responsive dual-drug delivery with NIR-II imaging-guided photothermal therapy (PTT), enabling triple-stimuli synergy of enzyme, light, and multi-drug co-activation. This modular design enables stable nanoassemblies with high drug-loading capacity and selective disassembly in enzyme-rich plaque microenvironments, achieving controlled dual-drug release exceeding 80 % within 72 h. Importantly, the unique integration of dual pharmacotherapy and NIR-II PTT within a single platform enables multi-level synergy: photothermal activation not only provides localized anti-inflammatory effects, but also promotes drug release and enhances plaque permeability, thereby amplifying the therapeutic benefits of both aspirin and lovastatin. In vitro, the platform facilitated targeted uptake, inhibited foam cell formation, and modulated cholesterol metabolism by regulating SREBP2 and ABCA1. In ApoE^-/- mice, the combined therapy significantly reduced plaque area by 53 %, improved lipid profiles, attenuated inflammatory cytokine expression, and enhanced vascular stability, as evidenced by increased collagen deposition and restored elastic fiber integrity. Compared with traditional nanotherapeutics, our green and biocompatible HA matrix combined with NIR-II photothermal modulation offers improved targeting, controlled release, and superior anti-inflammatory efficacy. This work demonstrates the potential of HALA@Ag₂S as a solid alternative to current therapies and a paradigm for green, multi-modal strategies in complex cardiovascular disease.