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Updated: Oct 16, 2025
Preparation of Neutrally-charged, pH-responsive Polymeric Nanoparticles for Cytosolic siRNA Delivery
Published on: May 2, 2019
Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy
Johan Karlsson1, Stephany Y Tzeng2, Shayan Hemmati2
1Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemistry-Ångström Laboratory, Uppsala University, Uppsala SE-75121, Sweden.
Photocrosslinked bioreducible nanoparticles (XbNPs) enhance RNA delivery by improving stability in blood and enabling efficient release inside cells. This breakthrough advances systemic nucleic acid therapeutics for cancer treatment.
Area of Science:
- Biomaterials Science
- Nanotechnology
- RNA Therapeutics
Background:
- Clinical translation of polymer-based nanocarriers for systemic RNA delivery is hindered by poor colloidal stability and inefficient intracellular RNA release.
- Existing nanocarriers often suffer from protein adsorption and limited endosomal escape, compromising therapeutic efficacy.
Purpose of the Study:
- To develop photocrosslinked bioreducible nanoparticles (XbNPs) for enhanced extracellular stability and intracellular RNA release.
- To overcome limitations in systemic RNA delivery for therapeutic applications.
Main Methods:
- Design of polymeric nanocarriers with hydrolytic ester bonds and disulfide bonds for triggered siRNA release.
- Photocrosslinking strategy to create XbNPs with shielded surface charge and reduced serum protein adsorption.
- In vitro evaluation of siRNA delivery and knockdown in glioma and melanoma cells under high-serum conditions.
- In vivo assessment of XbNPs for systemic delivery, tumor targeting, and therapeutic efficacy in melanoma lung metastasis models.
Main Results:
- XbNPs exhibited superior colloidal stability and reduced serum protein adsorption compared to non-crosslinked formulations.
- Enhanced cellular uptake and efficient endosomal escape were observed, leading to potent siRNA-mediated gene knockdown in cancer cells.
- Systemic administration of XbNPs demonstrated effective tumor targeting and tissue-mediated siRNA delivery beyond the liver, achieving robust in vivo knockdown in lung metastatic melanoma.
Conclusions:
- Biodegradable polymeric nanoparticles, enhanced by photocrosslinking, offer extended colloidal stability and efficient RNA delivery under physiological conditions.
- XbNPs represent a promising advancement in systemic delivery technologies for nucleic acid-based therapeutics, particularly for cancer treatment.
- The developed XbNPs strategy holds potential for overcoming key barriers in the clinical translation of RNA therapeutics.
