Atherosclerosis is a global disease with an extremely high morbidity and fatality rate, so it is necessary to develop effective treatments to reduce its impact. In this work, we successfully prepared a multifunctional drug-loaded nano-delivery system with pH-responsive, CD44-targeted, and chemical-photothermal synergistic treatment. Dendritic mesoporous silica nanoparticles capped with copper sulfide (CuS) were synthesized via an oil-water biphase stratification reaction system; these served as the carrier material and encapsulated the anticoagulant drug heparin (Hep). The pH-sensitive Schiff base bond was used as a gatekeeper and targeting agent to modify hyaluronic acid (HA) on the surface of the nanocarrier. HA coating endowed the nanocomposite with the ability to respond to pH and target CD44-positive inflammatory macrophages. Based on this multifunctional nanocomposite, we achieved precise drug delivery, controlled drug release, and chemical-photothermal synergistic treatment of atherosclerosis. The in vitro drug release results showed that the nanocarriers exhibited excellent drug-controlled release properties, and could release drugs in the weakly acidic microenvironment of atherosclerotic inflammation. Cytotoxicity and cell uptake experiments indicated that nanocarriers had low cytotoxicity against RAW 264.7 cells. Modification of HA to nanocarriers can be effectively internalized by RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Combining CuS photothermal treatment with anti-atherosclerosis chemotherapy showed better effects than single treatment in vitro and in vivo. In summary, our research proved that H-CuS@DMSN-NC-HA has broad application prospects in anti-atherosclerosis.