Visible-Light-Cured Carboxymethyl Chitosan Hydrogels with Tunable Crosslinking Density for Localized Photothermal and Photodynamic Therapy of Triple-Negative Breast Cancer

Injectable polymeric hydrogels capable of rapid in situ curing provide a promising platform for localized cancer therapy. Visible-light-cured carboxymethyl chitosan methacrylate (CMCSMA) hydrogels containing an indocyanine green–methyl-β-cyclodextrin inclusion complex (ICG-ic-CD) were developed for combined photothermal and photodynamic therapy of triple-negative breast cancer. Complexation with methyl-β-cyclodextrin reduced ICG aggregation and improved photostability under repeated near-infrared irradiation. Hydrogels containing 200 μg/mL ICG-ic-CD were prepared with different CMCSMA concentrations and visible-light curing times to regulate crosslinking density. Increasing polymer concentration or curing time decreased swelling and ICG-ic-CD release while increasing storage modulus, compressive strength, and injection force. Hydrogels cured for up to 60 s reached temperatures above 56 °C under 808-nm irradiation and generated reactive oxygen species, resulting in substantial photo-triggered cytotoxicity against 4T1 cells. Without irradiation, cell viability remained above 80%. Following intratumoral injection into 4T1 tumor-bearing mice, the hydrogels prolonged local ICG retention and maintained photothermal responses for up to 48 h. Formulations containing 4-6 wt% CMCSMA and cured for 10-60 s provided the most favorable balance among injectability, local retention, therapeutic-agent release, and tumor suppression. These results demonstrate that visible-light-controlled crosslinking enables tunable mechanical and release properties in injectable chitosan-based hydrogels and provides an effective local delivery platform for combined cancer phototherapy.