Niu, Ma, Zhu, and Sun et al. constructed circILNb, a circular RNA encoding a blocking anti-PD-L1 Nb and bioactive IL-15/IL-15Rα, which after purification via a novel biotin-avidin system, was delivered i.t. in LNPs. CircILNb enabled sustained robust in situ protein expression, tumor inhibition (dependent on activation of pre-existing CD8+ T and NK TILs and on IFNγ), and extended survival in four models of advanced “cold” tumors in mice, without systemic toxicity, and better than protein-based therapeutics. CircILNb-loaded DCs migrated to tdLNs to promote antigen-specific CD8+ T cell-mediated regression of distal tumors and metastases.
Contributed by Paula Hochman
ABSTRACT: The clinical translation of combined immunocytokine (IC) and immune checkpoint inhibitor (ICI) is constrained by relapse of advanced malignancies, systemic toxicities, and prohibitive research and synthesis costs. In this study, the circCV-B3 vector is constructed to enable scarless circular RNA (circRNA) engineering. The circILNb, engineered via the circCV-B3 vector, enables co-encoding of interleukin-15 (IL-15) and anti-PD-L1 nanobody (Nb). The circILNb is purified by biotin-avidin purification system (BAPS) and is encapsulated within lipid nanoparticles (LNPs). Intratumoral circILNb administration achieves in situ protein expression, achieving local tumor control. Furthermore, dendritic cells (DCs) load circILNb and migrate to tumor-draining lymph node (tdLN), where they prime antigen-specific CD8+ T cell activation, eliciting a robust systemic immune response. These findings highlight the potential of circCV-B3 vector and BAPS as a methodology for circRNA engineering and substantiate circILNb as non-protein-based therapeutic strategy for tumor immunotherapy.
Author Info: 1 - Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China.
2 - College of Education and Science, Chongq
Author Info: 1 - Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China.
2 - College of Education and Science, Chongqing Normal University, Chongqing 400047, China.
3 - Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: yangmingzhen0807@126.com.
4 - National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: qmzou2007@163.com.
5 - Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: lianjiqin@tmmu.edu.cn.
