CXCR4-targeted nitric oxide nanoparticles deliver PD-L1 siRNA for immunotherapy against glioblastoma

Hsin-Tzu Hsieh; Hsi-Chien Huang; Chieh-Wei Chung; Cheng-Chin Chiang; Tiffaney Hsia; Hsin-Fang Wu; Rui-Lin Huang; Chi-Shiun Chiang; Jane Wang; Tsai-Te Lu; Yunching Chen

doi:10.1016/j.jconrel.2022.10.047

CXCR4-targeted nitric oxide nanoparticles deliver PD-L1 siRNA for immunotherapy against glioblastoma

J Control Release. 2022 Dec:352:920-930. doi: 10.1016/j.jconrel.2022.10.047. Epub 2022 Nov 14.

Authors

Affiliations

¹ Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 30013, Taiwan.
² Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Chemical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.
³ Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
⁴ Department of Chemical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.
⁵ Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan. Electronic address: ttlu@mx.nthu.edu.tw.
⁶ Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan. Electronic address: yunching@mx.nthu.edu.tw.

PMID: 36334859
DOI: 10.1016/j.jconrel.2022.10.047

Abstract

While immunotherapy has emerged as a promising strategy to treat glioblastoma multiforme (GBM), the limited availability of immunotherapeutic agents in tumors due to the presence of the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment dampens efficacy. Nitric oxide (NO) plays a role in modulating both the BBB and tumor vessels and could thus be delivered to disrupt the BBB and improve the delivery of immunotherapeutics into GBM tumors. Herein, we report an immunotherapeutic approach that utilizes CXCR4-targeted lipid‑calcium-phosphate nanoparticles with NO donors (LCP-NO NPs). The delivery of NO resulted in enhanced BBB permeability and thus improved gene delivery across the BBB. CXCR4-targeted LCP-NO NPs delivered siRNA against the immune checkpoint ligand PD-L1 to GBM tumors, silenced PD-L1 expression, increased cytotoxic T cell infiltration and activation in GBM tumors, and suppressed GBM progression. Thus, the codelivery of NO and PD-L1 siRNA by these CXCR4-targeted NPs may serve as a potential immunotherapy for GBM.

Keywords: CXCR4; GBM; Gene therapy; Immunotherapy; Nitric oxide; PD-L1; siRNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen
Brain Neoplasms* / drug therapy
Cell Line, Tumor
Glioblastoma* / drug therapy
Humans
Immunotherapy
Nanoparticles*
Nitric Oxide / therapeutic use
RNA, Small Interfering / genetics
RNA, Small Interfering / therapeutic use
Receptors, CXCR4 / genetics
Tumor Microenvironment

Substances

B7-H1 Antigen
RNA, Small Interfering
Nitric Oxide
CXCR4 protein, human
Receptors, CXCR4