HA Self‐Assembled Dual‐Drug‐Loaded Nanoparticles: Integrating Multitargeted Tumor Therapy and Immune Microenvironment Remodeling via Phototherapy and Apoptosis

Activating the mitochondrial apoptosis pathway cancer therapy holds significant theoretical and clinical implications in cancer therapy. However, the complex regulation of tumorigenesis limits the efficacy of single‐target therapeutic approaches. This article introduces a novel antitumor nanoparticle (ICG‐HA‐ADH‐CBA‐TATKLA, IHTK), which combines glycosaminoglycan (hyaluronic acid, HA), proapoptotic fusion peptide (TAT‐KLA), and photothermal/photodynamic agent (indocyanine green, ICG). The nanoparticle enables precise tumor targeting and enhance ICG accumulation, generating substantial reactive oxygen species under near‐infrared irradiation. This process upregulates damage‐associated molecular patterns, including ATP, calreticulin (CRT), and HMGB1, to induce immunogenic cell death. Consequently, immune cell infiltration is promoted, and the tumor microenvironment (TME) is remodeled. Furthermore, the acidic TME triggers the release of TAT‐KLA (TK) through the nanoparticle's pH‐responsiveness, facilitating the rapid mitochondrial localization of TK. This mechanism disrupts mitochondrial membrane potential, enhances permeability, promotes Cytochrome C release, and activates caspase cascades to directly induce tumor cell apoptosis. In tumor‐bearing mice, IHTK effectively suppressed tumor progression and prolonged survival. In summary, IHTK, based on a multitarget regulation strategy, achieves TME‐responsive precision delivery, multipathway coordinated apoptosis induction, and immunomodulatory TME remodeling for synergistic therapeutic efficacy. This approach offers both a theoretical foundation and innovative insights for antitumor drug development.