Hyaluronic acid-modified Se@PDA@CDDP nanoplatform for synergistic chemo-photothermal therapy and immune activation via redox modulation

Abstract

Immunosuppressive and redox-buffered tumor microenvironments limit cisplatin efficacy in colorectal cancer (CRC) and blunt antitumor immunity. Herein, we engineer a hyaluronic-acid-modified, pH/redox/NIR-responsive nanoplatform (Se@PDA@HA@CDDP) by the in situ growth of selenium on polydopamine, followed by cisplatin loading and HA cloaking for CD44-mediated targeting. The nanoparticles exhibit uniform size distribution, robust colloidal stability, strong light-to-heat conversion, and GSH-consuming/ROS-amplifying activity, enabling on-demand drug release under acidic and GSH-rich conditions and NIR irradiation. In vitro, HA functionalization enhances cellular uptake and yields potent, NIR-augmented cytotoxicity characterized by mitochondrial depolarization (JC-1), apoptosis (Annexin V/PI), ROS burst (DCFH-DA), and GSH depletion while sparing normal cells. Mechanistically, Se@PDA@HA@CDDP treatment induces immunogenic cell death (ICD), as evidenced by calreticulin exposure and HMGB1 release, and concurrently activates NF-κB signaling (p-p65 upregulation). These events collectively promote macrophage polarization toward a pro-inflammatory M1 phenotype, accompanied by increased TNF-α and IL-6 secretion. In vivo imaging confirms HA-mediated tumor accumulation and superior photothermal performance; therapeutically, Se@PDA@HA@CDDP + NIR suppresses tumor growth, reduces angiogenesis (CD31) and proliferation (Ki67), and elevates apoptosis (TUNEL), alongside enhanced dendritic-cell maturation and intratumoral/lymph-node CD3⁺/CD8⁺/CD4⁺ T-cell infiltration. Histology and serum biochemistry reveal no overt organ damage or hepatic/renal dysfunction, supporting favorable biosafety. These findings establish Se@PDA@HA@CDDP as a mechanism-guided platform that couples targeted chemotherapy with photothermal and immune activation for efficient and safe CRC therapy.