Hyaluronic acid-engineered copper sulfide nanoparticles as immunomodulatory metal sulfide photothermal agents for macrophage-assisted osteosarcoma therapy.

Abstract

Metal sulfide nanomaterials have emerged as promising photothermal agents for cancer therapy owing to their strong near-infrared absorption, favorable biocompatibility, and tunable surface chemistry. However, insufficient tumor accumulation and limited immunological activation remain major obstacles restricting their therapeutic efficacy in solid tumors. Herein, we report a macrophage-assisted delivery strategy based on hyaluronic acid-engineered copper sulfide nanoparticles (HA@CuS NPs) for enhanced photothermal-immunotherapy against osteosarcoma. In this system, adoptively transferred RAW264.7 macrophages were intravenously administered to increase macrophage enrichment within the osteosarcoma microenvironment, while HA@CuS NPs were rationally designed to target both tumor cells and tumor-associated macrophages through HA-mediated cellular recognition. The HA-coated CuS nanoparticles displayed good colloidal stability, efficient near-infrared photothermal conversion, and enhanced cellular uptake by osteosarcoma cells and macrophages. Importantly, macrophages acted as cellular reservoirs for CuS nanoparticles, promoting tumor accumulation and improving intratumoral photothermal distribution. Under 808-nm laser irradiation, the combined macrophage/HA@CuS treatment produced stronger tumor heating and more effective osteosarcoma ablation than HA@CuS nanoparticles alone. Beyond direct photothermal killing, HA@CuS nanoparticles also remodeled the tumor immune microenvironment by promoting M1-like polarization of tumor-associated macrophages, increasing IL-12p40 secretion, reducing IL-10 levels, and enhancing cytotoxic T lymphocyte infiltration. These immune-regulatory effects further amplified the antitumor response induced by photothermal therapy. Collectively, this study demonstrates that HA-engineered copper sulfide nanoparticles can function not only as metal sulfide photothermal agents but also as immunomodulatory nanomaterials. The integration of macrophage-assisted tumor delivery with CuS-based photothermal therapy provides a promising strategy for improving the therapeutic efficacy of metal-based nanomedicine against osteosarcoma.