Multifunctional Near-Infrared-Responsive Silk Fibroin Nanomedicine for Tumor Treatment and Imaging.

Abstract

The complexity and heterogeneity of tumors make monotherapy inadequate for effective tumor elimination, highlighting the urgent need for multifunctional synergistic therapeutic strategies. In this study, a near-infrared (NIR)-responsive multimodal therapeutic nanoplatform (FSINPs) was constructed by simple adsorption of indocyanine green (ICG) and Fe³⁺ onto silk fibroin nanoparticles. Molecular docking showed that ICG binds stably to silk fibroin mainly via hydrogen bonds. Density functional theory (DFT) calculations predicted that Fe³⁺ strongly coordinates with the sulfonate groups of ICG and quenches ICG fluorescence via intermolecular charge transfer. Under conditions mimicking the acidic and high-glutathione tumor microenvironment, the ICG-Fe³⁺ coordination is disrupted, leading to fluorescence recovery of FSINPs. Fe³⁺ catalyzes the Fenton reaction to generate hydroxyl radicals (·OH), thereby achieving chemodynamic therapy (CDT). Upon 808 nm laser irradiation, ICG acts as a dual photosensitizer capable of both photothermal therapy (PTT) and photodynamic therapy (PDT), generating local hyperthermia with a photothermal conversion efficiency as high as 48.7% and producing singlet oxygen (¹O₂). The photothermal effect facilitates ·OH production, and CDT enhances photodynamic efficacy. The synergistic action of the three therapeutic modalities results in potent light-activated cytotoxicity toward tumor cells. In vivo experiments demonstrated that FSINPs enable tumor microenvironment-responsive fluorescence imaging for over 48 h and achieve complete tumor eradication in a 4T1 tumor model without obvious systemic toxicity. This study provides a new strategy for constructing activatable imaging and highly synergistic PTT/CDT/PDT-integrated silk fibroin-based nanomedicines and offers computational chemistry references for their rational design and development.