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

Abstract

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.

Toward Gene Transfer Nanoparticles as Therapeutics

“…[ 73 ] These bioreducible approaches benefit from quick intracellular release, within just minutes rather than hours or days, and help control release to be in the cytosol, rather than in endosomes or other intracellular compartments. [ 74 ]…”

Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery

“…Given the deficiencies of viral vectors, non-viral delivery systems are getting more attention due to their low toxicity, potential for targeted delivery, long-term stability, high loading, controllable FIGURE 2 | Simplified diagrams of some representative carriers applied for siRNA delivery in gliomas. siRNA carriers including polymer NPs (Karlsson et al, 2021), polymer micelles (Zhang et al, 2020a), dendrimer (Qiu et al, 2018), liposome (Hu et al, 2021), nanoemulsion (Teixeira et al, 2020), peptide decorated NPs (Zheng et al, 2019), gold NPs (Kumthekar et al, 2021), iron oxide NPs (Kievit et al, 2017) and exosome (Fu et al, 2021). chemical structure, low immunogenicity, easy mass production, and relatively low production costs.…”

“…In this way, various obstacles related to effective siRNA delivery can be resolved. In addition, cationic polymers with secondary and tertiary amines have shown significant buffering capacity, which helps the endosomal escape of siRNAs (Karlsson et al, 2021).…”

“…Such NPs can effectively achieve siRNA-mediated knockdown in gliomas and exhibit high serum stability, cell uptake, and tissue-mediated delivery to extrahepatic tissues. Moreover, the presence of both secondary and tertiary amines of these NPs leads to efficient buffering at low pH, leading to endosomal disruption, which achieves effective endosomal escape (Karlsson et al, 2021).…”

Applying Synthetic Biology with Rational Design to Nature’s Greatest Challenges: Bioengineering Immunotherapeutics for the Treatment of Glioblastoma

“…In the setting of this impressive repertoire of formats to choose from in designing therapeutics, new technologies that rapidly mine modelled combinations and screen candidates are essential to the advancement of this burgeoning field [29]. The rational design of protein-polymer conjugates has also been enhanced by the development of predictive tools and the breadth of synthetic tools that can attach polymers to proteins is rapidly expanding [21,38,42,43].…”