NIR-Triggered siRNA Release and Lysosomal Escape for Synergistic Photothermal Tumor Therapy
Myagmarsuren Baldan1,2,3, Shuang Zhang1,2,3, Qi Sun1,2,3
1School of Pharmaceutical Sciences, Capital Medical University, Beijing, People's Republic of China.
Background:
Resistance to traditional treatments has spurred research into innovative therapeutic approaches for tumors. Among these innovative treatments, photothermal therapy (PTT) has gained increasing attention for its use of photothermal agents (PTAs) to convert light into heat for localized tumor ablation. However, PTT faces limitations due to heat shock protein 70 (HSP70)-mediated resistance in tumor cells. Combining PTT via indocyanine green (ICG) with siRNA HSP70 could reduce the thermal resistance of the tumor, thereby enhancing treatment efficacy. Albumin-based nanoparticles (NPs) can effectively deliver ICG and siRNA into tumor cells. When exposed to near-infrared (NIR) light, these nanoparticles trigger lysosomal escape and release, further enhancing gene silencing activity.
Methods:
This study aimed to develop a biocompatible delivery system, HSA@ICG/siRNA NPs, for photothermal-enhanced tumor therapy. The nanoparticles were characterized for size, charge, surface functionalization, and photoconversion properties. In vitro antitumor efficacy was evaluated using MTT assay, calcein AM/PI staining, RT-PCR, and Western blot in 4T1 tumor cells. In vivo, we assessed photothermal effects, biodistribution, tumor inhibition, and biosafety following irradiation.
Results:
Characterization confirmed the successful synthesis of uniform, stable HSA@ICG/siRNA NPs with effective photothermal conversion properties. Cellular uptake studies revealed high siRNA internalization, with laser-induced lysosomal escape enhancing cytoplasmic delivery. In vitro, gene silencing reduced mRNA and protein levels by 82.8% and 65%, respectively. In vivo, local tumor temperature increased to 42°C within 3 minutes, indicating a mild but effective photothermal effect. Tumor inhibition rates were 50.00% ± 9.16% for HSA@ICG and 71.26% ± 7.92% for HSA@ICG/siRNA, demonstrating enhanced tumor suppression. The treatment achieved sustained tumor targeting with minimal off-target toxicity.
Conclusion:
As a dual-function photothermal therapy agent, HSA@ICG/siRNA NPs combine targeted gene silencing with photothermal effects, demonstrating significant therapeutic promise. This integrated approach addresses tumor resistance, offering a potential advancement in cancer treatment strategies.
Insights
This study developed albumin-based nanoparticles carrying indocyanine green (ICG) and siRNA targeting heat shock protein 70 (HSP70) to overcome tumor resistance. The nanoparticles effectively silenced HSP70 and enhanced photothermal therapy, significantly inhibiting tumor growth with minimal toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Photothermal therapy (PTT) shows promise for tumor ablation but faces resistance mediated by heat shock protein 70 (HSP70).
- Combining PTT with gene silencing of HSP70 can enhance therapeutic efficacy.
- Albumin-based nanoparticles (NPs) offer a platform for co-delivery of photothermal agents like indocyanine green (ICG) and siRNA.
Purpose of the Study:
- To develop and evaluate HSA@ICG/siRNA NPs as a biocompatible system for combined photothermal and gene silencing therapy.
- To investigate the efficacy of these NPs in overcoming tumor resistance and enhancing cancer treatment.
- To assess the in vitro and in vivo performance of the developed nanotherapeutics.
Main Methods:
- Synthesis and characterization of albumin-based nanoparticles (HSA@ICG/siRNA NPs) for size, charge, and photoconversion.
- In vitro evaluation of cellular uptake, lysosomal escape, gene silencing (mRNA/protein reduction), and cytotoxicity in 4T1 tumor cells.
- In vivo assessment of photothermal effects, biodistribution, tumor inhibition rates, and biosafety following near-infrared (NIR) light irradiation.
Main Results:
- HSA@ICG/siRNA NPs were successfully synthesized with uniform size and effective photothermal properties.
- In vitro studies demonstrated efficient siRNA delivery, enhanced cytoplasmic release, and significant reduction in HSP70 mRNA (82.8%) and protein (65%).
- In vivo, NIR irradiation induced a mild hyperthermia (42°C), leading to enhanced tumor inhibition (71.26% ± 7.92%) compared to PTT alone (50.00% ± 9.16%) with minimal off-target toxicity.
Conclusions:
- HSA@ICG/siRNA NPs act as a dual-function agent, combining targeted gene silencing with photothermal therapy.
- This integrated approach effectively overcomes tumor resistance and demonstrates significant therapeutic potential.
- The developed nanocarrier represents a promising advancement in multimodal cancer treatment strategies.
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