Metal-Organic Framework Nanoplatform Synergizes Fenton-Driven Ferroptosis and Photodynamic Apoptosis for Enhanced Hepatocellular Carcinoma Therapy

Background: Hepatocellular carcinoma (HCC) is notorious for its dismal prognosis and resistance to conventional therapies. The integration of multiple cell death mechanisms emerges as a promising strategy to combat the heterogeneity of this malignancy.

Purpose: Herein, we engineered a multifunctional nanoplatform, TPMIL101-TCPP@Lip-HA, by encapsulating the Photosensitizer TCPP and chemotherapeutic agent triptolide (TP) within a metal-organic framework (MIL101), followed by surface modification with liposomes and hyaluronic acid. This sophisticated drug delivery system capitalizes on the enhanced permeability and retention effect to achieve tumor-specific accumulation.

Methods: Upon reaching the tumor site, TPMIL101-TCPP@Lip-HA undergoes gradual disintegration, releasing its therapeutic payload. The tumor microenvironment facilitates the reduction of Fe³⁺ to Fe²⁺, triggering Ferroptosis through the Fenton reaction. Simultaneously, laser irradiation activates TCPP to generate cytotoxic Reactive Oxygen Species, initiating photodynamic therapy-induced Apoptosis. The concomitant accumulation of lipid peroxides synergistically amplifies the ferroptotic cascade.

Results: In vitro/in vivo studies confirm potent anti-HCC efficacy with reduced TP toxicity. Mechanistic studies elucidate that TPMIL101-TCPP@Lip-HA orchestrates Ferroptosis through modulation of iron storage and lipid oxidation proteins, while concurrently inducing Apoptosis via the cytochrome c/Apaf-1/Caspase signaling axis.

Conclusion: These findings collectively underscore TPMIL101-TCPP@Lip-HA as a potent therapeutic nanoplatform capable of arresting HCC progression.