Citation: Cheng Huang, Wanqin Zeng, Kunhong Zhong, Xing Duan, Yi Liu, Qingqing Tian, Liangxue Zhou, Yuelong Wang, Chunlai Nie, Aiping Tong. A novel ionizable lipid nanoparticle platform for circular RNA-encoded PD-L1×CD3 bispecific antibodies elicits potent antitumor immunity[J]. Chinese Chemical Letters, ;2026, 37(8): 112322. doi: 10.1016/j.cclet.2025.112322 shu

A novel ionizable lipid nanoparticle platform for circular RNA-encoded PD-L1×CD3 bispecific antibodies elicits potent antitumor immunity

Cheng Huang ^{a, 1} ,
Wanqin Zeng ^{a, 1} ,
Kunhong Zhong ^{a, b, 1} ,
Xing Duan ^a ,
Yi Liu ^b ,
Qingqing Tian ^a ,
Liangxue Zhou ^b ,
Yuelong Wang ^{b, *,} ,
Chunlai Nie ^{a, *,} ,
Aiping Tong ^{a, c, *,}

a.
State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
b.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610044, China
c.
Tianfu Jincheng Laboratory, Chengdu 610093, China

yuelongwang@scu.edu.cn

niecl1022@scu.edu.cn

aipingtong@scu.edu.cn

Received Date: 30 October 2025
Revised Date: 23 December 2025
Accepted Date: 24 December 2025
Available Online: 24 December 2025

Figures(5)

Linear mRNA-encoded bispecific T cell engagers (BiTEs) have shown promising efficacy in cancer treatment; however, their clinical translation remains constrained by poor stability and transient protein expression. To overcome these limitations, we engineered a circular RNA (cRNA) encoding PD-L1×CD3 BiTEs using permuted intron-exon splicing and CVB3-IRES elements, and encapsulated it into novel ionizable lipid nanoparticles (D1LNPs) synthesized via a streamlined one-step reaction. This platform, termed D1LNP@cRNA^BiTEs, achieved robust and sustained in vivo expression of the BiTEs, significantly outperforming conventional linear mRNA formulations. In murine models of colorectal cancer, monotherapy with D1LNP@cRNA^BiTEs potently inhibited tumor growth, enhanced CD8⁺ T-cell infiltration into the tumor microenvironment, and elevated levels of proinflammatory cytokines. Furthermore, ELISpot analysis confirmed the enhancement of systemic antigen-specific T cell responses. The D1LNPs delivery system also demonstrated excellent stability and favorable safety profile. In conclusion, our study provides compelling evidence for the D1LNPs@cRNA platform as a potent and scalable strategy for cancer immunotherapy, effectively addressing key challenges of RNA stability and delivery.
- Cancer immunotherapy,
- Circular RNA,
- Lipid nanoparticles,
- Bispecific T cell-engagers,
- mRNA delivery,
- Tumor microenvironment
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沈阳化工大学材料科学与工程学院沈阳 110142