Polydopamine Decorated Hyaluronic Acid Clusters for Tumor Cell Targeting Combination Therapy via Template Self‐Consumption Methods

Photothermal-chemodynamic-chemotherapy (PTT-CDT-CT) combination therapy significantly enhances the therapeutic efficacy against tumors. However, synthesizing PTT-CDT-CT nanosystems is complex, typically requiring the preparation and conjugation of three components into a single carrier. To overcome this challenge, a facile template self-consumption method is developed. In this approach, hyaluronic acid (HA), recognized for its tumor cell targeting properties, chelates with Cu²⁺ to form Cu-HA, which then transforms into CuO₂@HA cluster templates. These templates self-consume gradually, producing ·OH and Cu²⁺, which catalyze the rapid polymerization of dopamine and coordinate with polydopamine respectively, enhancing the photothermal conversion efficiency. After gossypol loading, GPDA@HA clusters are formed, achieving high gossypol loading efficiency due to π-π stacking between gossypol and PDA, as well as coordination between gossypol and Cu²⁺. The GPDA@HA clusters are effectively internalized by tumor cells through endocytosis, mediating the synergistic damage or inhibition of intracellular proteins, and nucleic acids against tumor cells via PTT, CDT, and CT. Crucially, the synergism of PTT-CDT-CT combination therapy far surpasses those of a single modality. This work introduces a new pathway for the synthesis of PTT-CDT-CT nanosystems, avoiding the conventional synthesis and loading of different therapeutic agents, and provides insights into developing personalized drug combination therapies with high efficacy.