TY - JOUR
T1 - Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy
AU - Karlsson, Johan
AU - Tzeng, Stephany Y.
AU - Hemmati, Shayan
AU - Luly, Kathryn M.
AU - Choi, Olivia
AU - Rui, Yuan
AU - Wilson, David R.
AU - Kozielski, Kristen L.
AU - Quiñones-Hinojosa, Alfredo
AU - Green, Jordan J.
N1 - Funding Information:
J.K. was supported by the Swedish Research Council International Postdoc grant (2016‐06675). The authors thank the NIH (P41EB028239, R01CA228133, R01CA195503, and R37CA246699) for support, in part, of this work.
Publisher Copyright:
© 2021 The Authors. Advanced Functional Materials published by Wiley-VCH GmbH
PY - 2021/4/22
Y1 - 2021/4/22
N2 - 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.
AB - 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.
KW - bioreducible
KW - crosslinking
KW - nanoparticles
KW - siRNA
KW - stimuli-responsive polymers
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U2 - 10.1002/adfm.202009768
DO - 10.1002/adfm.202009768
M3 - Article
C2 - 34650390
AN - SCOPUS:85101202653
SN - 1616-301X
VL - 31
JO - Advanced Functional Materials
JF - Advanced Functional Materials
IS - 17
M1 - 2009768
ER -