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Metal-Organic Framework Nanoplatform Synergizes Fenton-Driven Ferroptosis and Photodynamic Apoptosis for Enhanced
Shasha Kong1,2, Hongmei Lin3,4, Yuling Liu1
1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China.
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.
Insights
A novel nanoplatform, TPMIL101-TCPP@Lip-HA, effectively treats hepatocellular carcinoma (HCC) by combining ferroptosis and photodynamic therapy. This approach overcomes drug resistance and reduces toxicity for improved HCC treatment.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Hepatocellular carcinoma (HCC) presents a significant clinical challenge due to poor prognosis and treatment resistance.
- Combining multiple cell death pathways offers a promising strategy to address HCC heterogeneity.
Purpose of the Study:
- To engineer a multifunctional nanoplatform (TPMIL101-TCPP@Lip-HA) for targeted HCC therapy.
- To leverage the enhanced permeability and retention (EPR) effect for tumor-specific drug accumulation.
Main Methods:
- Encapsulation of photosensitizer TCPP and chemotherapeutic triptolide (TP) within a metal-organic framework (MIL101).
- Surface modification with liposomes and hyaluronic acid for targeted delivery.
- Induction of ferroptosis via Fenton reaction and photodynamic therapy-induced apoptosis upon laser irradiation.
Main Results:
- TPMIL101-TCPP@Lip-HA demonstrated potent anti-HCC efficacy in vitro and in vivo.
- The nanoplatform induced ferroptosis by modulating iron metabolism and apoptosis via the cytochrome c signaling pathway.
- Reduced toxicity of triptolide was observed compared to conventional administration.
Conclusions:
- TPMIL101-TCPP@Lip-HA is a potent nanotherapeutic agent for hepatocellular carcinoma.
- This dual-modal therapeutic strategy effectively arrests HCC progression by inducing combined ferroptosis and apoptosis.
