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From Physical Amplification to Biological Effect: The Evolving Landscape of Nucleic Acid Nanomedicines in Radio-Immunotherapy

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From Physical Amplification to Biological Effect: The Evolving Landscape of Nucleic Acid Nanomedicines in Radio-Immunotherapy

Chuxuan Long 1,† Yi Zhu 1,† Namei Ji 1,† Xiumei Ma 2,* Chunlin Shao 3,* Yuexia Xie 1,*

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1
Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu-Jian Road, Shanghai 200127, China
2
Department of Radiation Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu-Jian Road, Shanghai 200127, China
3
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.

Received: 26 May 2026 Revised: 09 June 2026 Accepted: 16 July 2026 Published: 31 July 2026

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© 2026 The authors. This is an open access article under the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

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iMed 2026, 1(1), 10007; DOI: 10.70322/iMed.2026.10007
ABSTRACT: Radiotherapy (RT) remains a mainstay of cancer treatment, but its efficacy is limited by radioresistance and immunosuppression. Nucleic acid therapeutics, including siRNA, microRNA modulators, antisense oligonucleotides, aptamers, CpG oligodeoxynucleotides, and CRISPR systems, can remodel tumor responses at multiple levels. Nanotechnology enables their precise delivery, protection, and spatiotemporal activation. This review synthesizes recent advances in nucleic acid-enabled radiosensitization across four dimensions: (1) precise delivery via passive/active targeting and radiation-triggered release; (2) target selection from dominant-node inhibition to coordinated network regulation; (3) immune remodeling from checkpoint blockade to active immune instruction; and (4) multimodal integration where RT serves as a biological switch. We formally define programmable radio-nanomedicine as the co-design of nucleic acid cargo, carrier logic, activation trigger, and radiation schedule so that irradiation acts as a context-defining event. Translational barriers and a framework for next-generation design are discussed.
Keywords: Radiotherapy; Radiosensitization; Nucleic acid nanomedicine; Tumor microenvironment; Radio-immunotherapy

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