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Electrostatic Attractive Self-Delivery of siRNA and Light-Induced Self-Escape for Synergistic Gene Therapy
Yuxin Yang1, Haijun Ning1, Tianping Xia1
1State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, 116024, China.
Abstract:
Small interfering RNA (siRNA) holds immense promise for suppressing gene expression and treating various life-threatening diseases, including cancer. However, efficient delivery and lysosomal escape remain critical challenges that hinder the therapeutic effectiveness of siRNA. Herein, cationic photosensitizer (NB-Br) is grafted onto polo-like kinase 1 (PLK1) siRNA to form an amphiphilic siRNA-photosensitizer conjugate (siPLK1-NB), which can self-assemble into nanoparticles (siPLK1-NB NPs) via electrostatic attraction. Notably, siPLK1-NB NPs exhibit rapid and efficient cell endocytosis, as well as outstanding tumor-targeting property in multiple tumor-bearing mice models. When siPLK1-NB NPs are located inside tumor cell lysosomes, the generated reactive oxygen species (ROS) after photoactivation can disrupt the lysosome membrane structure and facilitate siRNA escape from lysosomes. Under light irradiation, siPLK1-NB NPs can downregulate PLK1 expression and induce photodynamic killing, effectively inhibiting tumor cell growth both in vitro and in vivo. Consequently, this study provides a novel design strategy for carrier-free siRNA delivery systems. As far as it is known, this is the first report of a carrier-free siRNA delivery system based on electrostatic attraction.
Insights
This study presents a novel carrier-free nanoparticle system for delivering small interfering RNA (siRNA) to target cancer cells. The system enhances siRNA delivery and release, improving therapeutic outcomes for cancer treatment.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Molecular Biology
Background:
- Small interfering RNA (siRNA) is a promising therapeutic agent for gene silencing, particularly in cancer treatment.
- Key challenges for siRNA therapeutics include efficient cellular delivery and overcoming endosomal/lysosomal entrapment.
- Developing carrier-free delivery systems can simplify formulation and potentially improve therapeutic efficacy.
Purpose of the Study:
- To develop a novel, carrier-free nanoparticle system for enhanced siRNA delivery and therapeutic application.
- To investigate the potential of a cationic photosensitizer-siRNA conjugate for tumor targeting and photodynamic therapy.
- To overcome the limitations of lysosomal entrapment for improved siRNA bioavailability.
Main Methods:
- Grafting a cationic photosensitizer (NB-Br) onto polo-like kinase 1 (PLK1) siRNA to create an amphiphilic conjugate (siPLK1-NB).
- Self-assembly of the conjugate into nanoparticles (siPLK1-NB NPs) through electrostatic attraction.
- Evaluation of cellular uptake, tumor targeting, lysosomal escape via reactive oxygen species (ROS) generation upon photoactivation, and in vitro/in vivo anti-tumor efficacy.
Main Results:
- siPLK1-NB NPs demonstrated rapid and efficient cell endocytosis and significant tumor targeting in vivo.
- Photoactivated ROS generation facilitated lysosomal escape of siRNA from tumor cells.
- The system effectively downregulated PLK1 expression, induced photodynamic killing, and inhibited tumor growth both in vitro and in vivo.
- This represents the first reported carrier-free siRNA delivery system utilizing electrostatic attraction.
Conclusions:
- The developed carrier-free siRNA-photosensitizer nanoparticles offer a promising strategy for cancer therapy.
- This approach overcomes critical barriers in siRNA delivery, including cellular uptake and lysosomal escape.
- The system integrates gene silencing with photodynamic therapy for enhanced anti-tumor effects.
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