期刊
ACS NANO
卷 15, 期 3, 页码 4576-4593出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.0c08694
关键词
siRNA; systemic delivery; soft; noncationic; polyphenol nanocapsules; solid tumors; immune checkpoint blockade
类别
资金
- National Institutes of Health [R01 CA232419, R01 CA199663, R01 CA258737]
- National Science Foundation [CBET-1705560]
- Indiana Clinical and Translational Sciences Institute - National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award [UL1 TR002529]
The development of Nanosac, a soft polyphenol nanocapsule without positive charges, has shown promising results in improving systemic delivery of siRNA to solid tumors by enhancing extravasation and penetration, ultimately leading to efficient gene silencing and tumor growth suppression through immune checkpoint blockade.
For systemic delivery of small interfering RNA (siRNA) to solid tumors, the carrier must circulate avoiding premature degradation, extravasate and penetrate tumors, enter target cells, traffic to the intracellular destination, and release siRNA for gene silencing. However, existing siRNA carriers, which typically exhibit positive charges, fall short of these requirements by a large margin; thus, systemic delivery of siRNA to tumors remains a significant challenge. To overcome the limitations of existing approaches, we have developed a carrier of siRNA, called Nanosac, a noncationic soft polyphenol nanocapsule. A siRNA-loaded Nanosac is produced by sequential coating of mesoporous silica nanoparticles (MSNs) with siRNA and polydopamine, followed by removal of the sacrificial MSN core. The Nanosac recruits serum albumin, co-opts caveolae-mediated endocytosis to enter tumor cells, and efficiently silences target genes. The softness of Nanosac improves extravasation and penetration into tumors compared to its hard counterpart. As a carrier of siRNA targeting PD-L1, Nanosac induces a significant attenuation of CT26 tumor growth by immune checkpoint blockade. These results support the utility of Nanosac in the systemic delivery of siRNA for solid tumor therapy.
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