Sheddable Ternary Nanoparticles for Tumor Acidity-Targeted siRNA Delivery

Abstract

Drug delivery systems for cancer therapy usually need to be sterically stabilized by a poly(ethylene glycol) (PEG) layer during blood circulation to minimize nonspecific interactions with serum components. However, PEGylation significantly reduces cellular uptake of the delivery systems after they accumulate at the tumor site, which markedly impairs the in vivo antitumor efficiency. Here, we develop a ternary small interfering RNA (siRNA) delivery system with tumor acidity-activated sheddable PEG layer to overcome the challenge. The sheddable nanoparticle is fabricated by introducing a tumor acidity-responsive PEGylated anionic polymer to the surface of positively charged polycation/siRNA complexes via electrostatic interaction. We show clear evidence that introducing the PEGylated anionic polymer to the surface of a nanoparticle markedly reduces its nonspecific interactions with protein. We further demonstrate that the nanoparticle is capable of deshielding the PEG layer at the slightly acidic tumor extracellular microenvironment to facilitate the delivery of siRNA to the tumor cells after accumulation at the tumor site. Accordingly, this promotes the RNA-interfering efficiencies and enhances the inhibition of tumor growth. Such delivery system with the ability to deshield the PEG layer at the target tissues has remarkable potential in cancer therapy.

Genome Editing for Cancer Therapy: Delivery of Cas9 Protein/sgRNA Plasmid via a Gold Nanocluster/Lipid Core–Shell Nanocarrier

“…Previous reports indicated that the depletion of Plk1 might inhibit tumor cell proliferation and division and lead to tumor cell apoptosis 23, 24, 25. In this study, the LGCP treatment resulted in 19.4% apoptosis among A375 cells, which was about tenfold higher than that of the GCP group (1.9%).…”

“…The overexpression of Plk1 was found in many tumor tissues and model tumor cells, e.g., A375 cells. The inhibition of Plk1 expression can cause apoptosis of tumor cells, which provides a good strategy for tumor therapy 23, 24, 25. Thus, LGCP was designed to bring the powerful gene editing toolbox (Cas9 protein/sgPlk1 plasmid, here “sgPlk1 plasmid” represents the plasmid encoding only the single guide RNA, without Cas9 in this paper) into tumor cells and tissues to inhibit tumor progression with high efficiency.…”

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

“…Last, sustainable dosing at the tumor site is necessary, given the dynamic nature of malignant tumor genetic/epigenetic adaptations to therapy. Numerous nano constructs have been designed to address each of these elements (32,34,35,68,69); our approach comprehensively combines the favorable benefits of several modalities. It builds on the blood vessel-targeting capacity of the customizable 7C1 lipopolymeric nano vehicle, which has excellent safety profiles (14,15,23,70).…”

Dual Responsive, Stabilized Nanoparticles for Efficient In Vivo Plasmid Delivery

“…In summary, we present here a novel block-statistical copolymer, PCL 40 -SS-P{(GMA-TEPA) 58 -st-OEGMA 10 }, that provides one solution to the in vivo stability versus high transfection efficiency dilemma. This material combines reversible hydrophobization for enhanced polyplex stability in extracellular environments and statistical hydrophilization for efficient plasmid and siRNA release inside cells.…”