Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy

• Published in: Advanced functional materials 2021-04, Vol.31 (17), p.n/a
• Main Authors: Karlsson, Johan, Tzeng, Stephany Y., Hemmati, Shayan, Luly, Kathryn M., Choi, Olivia, Rui, Yuan, Wilson, David R., Kozielski, Kristen L., Quiñones‐Hinojosa, Alfredo, Green, Jordan J.
• Format: Article
• Language: English
• Subjects: Amines; Biodegradability; bioreducible; Cancer; crosslinking; Escape systems; Materials science; Melanoma; Nanoparticles; Nucleic acids; Ribonucleic acid; RNA; Serum proteins; siRNA; Stability; stimuli-responsive polymers; Surface charge
• ISSN: 1616-301X; 1616-3028; 1616-3028
• DOI: 10.1002/adfm.202009768

Clinical translation of polymer‐based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA‐mediated knockdown in both glioma and melanoma cells in high‐serum conditions compared to non‐crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue‐mediated siRNA delivery beyond the liver, unlike conventional nanoparticle‐based delivery. These attributes of XbNPs facilitate robust siRNA‐mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid‐based therapeutics. Nanocarriers are engineered to realize the potential of RNA therapeutics. This work reports the design of photocrosslinked bioreducible nanoparticles (XbNPs) for stable small interfering RNA (siRNA) encapsulation in high‐serum conditions, shielded surface charge, efficient intracellular trafficking, and triggered cytosolic RNA release. These attributes of XbNPs lead to robust siRNA‐mediated knockdown in cancer cells and potent systemic siRNA delivery to tumors in the lungs.