Hypoxia-reinforced antitumor RNA interference mediated by micelleplexes with programmed disintegration
Xudong Li1, Xiangnan Xu2, Ke Huang3
1Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou 215123, China.
Acta Biomaterialia
|June 6, 2022
Summary
Researchers developed micelleplexes for programmed siRNA delivery, overcoming biological barriers. This hypoxia-reinforced strategy enhances anti-cancer efficacy by combining RNA interference with photodynamic therapy.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cancer Therapy
Background:
- Polycation-mediated siRNA delivery faces systemic and cellular barriers.
- Conflicting material properties are required to overcome these barriers.
- Micelleplexes (MPs) offer a potential solution for controlled siRNA delivery.
Purpose of the Study:
- To develop micelleplexes capable of programmed disintegration for efficient siRNA delivery against XIAP (siXIAP).
- To create a hypoxia-reinforced strategy for enhanced anti-cancer efficacy.
- To overcome multiple barriers in systemic siRNA delivery.
Main Methods:
- Assembled MPs from azobenzene-crosslinked oligoethylenimine (AO), acid-transformable diblock copolymer PPDHP with a photosensitizer, and siXIAP.
- Utilized electrostatic and hydrophobic interactions for MP stability.
- Exploited endolysosomal acidity and light irradiation for programmed disintegration and siRNA release.
Main Results:
- MPs demonstrated high salt and serum stability, prolonging circulation and promoting tumor accumulation.
- Endolysosomal acidity triggered PPDHP shedding, facilitating endolysosomal escape.
- Light irradiation aggravated hypoxia, degrading AO, releasing siXIAP, and potentiating XIAP silencing.
- Combined siXIAP-mediated apoptosis and ROS generation showed pronounced anti-cancer efficacy in vitro and in vivo.
Conclusions:
- Developed a hypoxia-instructed strategy for programmed siRNA delivery, overcoming multiple barriers.
- Demonstrated the potential of hypoxia-degradable polycations for hypoxia-reinforced RNAi.
- Provided an effective strategy for systemic siRNA delivery in cancer therapy.
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