A fully biodegradable spherical nucleic acid nanoplatform for self-codelivery of doxorubicin and miR122 for innate and adaptive immunity activation

Ming-Chao Jiang; Zhou-Long Fang; Jin-Yan Zhang; Wei Ma; Luan-Feng Liao; Cui-Yun Yu; Hua Wei

doi:10.1016/j.actbio.2024.04.013

A fully biodegradable spherical nucleic acid nanoplatform for self-codelivery of doxorubicin and miR122 for innate and adaptive immunity activation

Acta Biomater. 2024 Apr 16:S1742-7061(24)00186-7. doi: 10.1016/j.actbio.2024.04.013. Online ahead of print.

Authors

Ming-Chao Jiang¹, Zhou-Long Fang¹, Jin-Yan Zhang¹, Wei Ma¹, Luan-Feng Liao¹, Cui-Yun Yu², Hua Wei³

Affiliations

¹ Hengyang Medical School, School of Resources Environment and Safety Engineering, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, University of South China, Hengyang 421001, China.
² Affiliated Hospital of Hunan Academy of Chinese Medicine Hunan, Academy of Chinese Medicine, Changsha 410013, China; Hengyang Medical School, School of Resources Environment and Safety Engineering, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. Electronic address: yucuiyunusc@hotmail.com.
³ Hengyang Medical School, School of Resources Environment and Safety Engineering, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, University of South China, Hengyang 421001, China. Electronic address: weih@usc.edu.cn.

PMID: 38614414
DOI: 10.1016/j.actbio.2024.04.013

Abstract

Facile construction of a fully biodegradable spherical nucleic acid (SNA) nanoplatform is highly desirable for clinical translations but remains rarely explored. We developed herein the first polycarbonate-based biodegradable SNA nanoplatform for self-codelivery of a chemotherapeutic drug, doxorubicin (DOX), and a human liver-specific miR122 for synergistic chemo-gene therapy of hepatocellular carcinoma (HCC). Ring-opening polymerization (ROP) of a carbonate monomer leads to a well-defined polycarbonate backbone for subsequent DOX conjugation to the pendant side chains via acidic pH-cleavage Schiff base links and miR122 incorporation to the chain termini via click coupling, affording an amphiphilic polycarbonate-DOX-miR122 conjugate, PBis-Mpa₃₀-DOX-miR122 that can self-assemble into stabilized SNA. Besides the desired biodegradability, another notable merit of this nanoplatform is the use of miR122 not only for gene therapy but also for enhanced innate immune response. Together with the ICD-triggering effect of DOX, PBis-Mpa₃₀-DOX-miR122 SNA-mediated DOX and miR122 codelivery leads to synergistic immunogenicity enhancement, resulting in tumor growth inhibition value (TGI) of 98.1 % significantly higher than those of the groups treated with only drug or gene in a Hepa1-6-tumor-bearing mice model. Overall, this study develops a useful strategy toward biodegradable SNA construction, and presents a drug and gene-based self-codelivery SNA with synergistic immunogenicity enhancement for efficient HCC therapy. STATEMENT OF SIGNIFICANCE: Facile construction of a fully biodegradable SNA nanoplatform is useful for in vivo applications but remains relatively unexplored likely due to the synthetic challenge. We report herein construction of a polycarbonate-based SNA nanoplatform for co-delivering a chemotherapeutic drug, DOX, and a human liver-specific miR-122 for synergistic HCC treatment. In addition to the desired biodegradability properties, this SNA nanoplatform integrates DOX-triggered ICD and miR-122-enhanced innate immunity for simultaneously activating adaptive and innate immunities, which leads to potent antitumor efficiency with a TGI value of 98.1 % in a Hepa1-6-tumor-bearing mice model.

Keywords: Biodegradation; HCC; Immunogenic cell death; SNA; Synergistic immunogenicity enhancement.