肿瘤细胞治疗研究
英文原题：Circular Logic: Engineering Next-Generation Circular RNA Therapeutics for Precision Oncology.
RNA 疗法的拓扑结构正逐渐成为精准肿瘤学中的一个关键设计维度。
RNA 疗法的拓扑结构正逐渐成为精准肿瘤学中的一个关键设计维度。与线性 mRNA 不同，环状 RNA（circRNA）缺乏游离末端，因而具有对核酸外切酶降解的卓越抗性，并能够实现持续数天至数周的蛋白表达。除了作为工程化治疗药物使用外，内源性 circRNA 在生物体液中表现出与癌症相关的表达模式及持久性，这支持其在肿瘤生物学中的互补作用以及作为诊断和纵向疾病监测候选生物标志物的潜力。本综述认为，环状拓扑结构应被视为一个主动的药理学变量，而不仅仅是稳定性增强手段。我们剖析了不依赖帽的翻译起始方面的最新进展，包括 IRES 元件和 m 6 A 驱动机制、用于多表位疫苗设计的滚环翻译，以及整合肿瘤微环境线索（如 miRNA 特征）的可编程稳定性回路。递送创新同样具有变革性：抗体引导的脂质纳米颗粒和工程化细胞外囊泡使 RNA 递送日益具有选择性，而局部储库制剂和器官选择性全身给药途径则拓展了治疗覆盖范围。安全性考量被重新评估为双刃工具——先天免疫原性可作为癌症疫苗的自我佐剂，而背剪接连接新抗原既提供疫苗机会，也带来耐受性风险。无瘢痕环化、拓扑结构敏感纯化、dsRNA 去除和冻干制剂方面的最新进展已开始解决关键生产瓶颈，尽管临床规模回收和工艺可扩展性仍缺乏充分表征。关键应用包括circRNA癌症疫苗、瞬时CAR-T/NK细胞工程、抑癌基因替代以及circRNA编码的双特异性T细胞衔接器。该领域目前需要实时药代动力学追踪、可重复且可规模化的生产、经过验证的液体活检检测方法以及针对特定适应症的监管路径，以将circRNA从实验室推向临床。
The topology of RNA therapeutics is emerging as a critical design dimension in precision oncology. Unlike linear mRNA, circular RNA (circRNA) lacks free ends, conferring exceptional resistance to exonuclease degradation and enabling sustained protein expression for days to weeks. Beyond their use as engineered therapeutics, endogenous circRNAs exhibit cancer-associated expression patterns and persistence in biofluids, supporting complementary roles in tumor biology and as candidate biomarkers for diagnosis and longitudinal disease monitoring. This review argues that circular topology should be viewed as an active pharmacologic variable, not merely a stability enhancement. We dissect recent advances in cap-independent translation initiation, including IRES elements and m 6 A-driven mechanisms, rolling-circle translation for multi-epitope vaccine design, and programmable stability circuits that integrate tumor-microenvironment cues such as miRNA signatures. Delivery innovations are equally transformative: antibody-guided lipid nanoparticles and engineered extracellular vesicles enable increasingly selective RNA delivery, while local depot formulations and organ-selective systemic routes expand therapeutic reach. Safety considerations are re-evaluated as double-edged tools-innate immunogenicity can serve as a self-adjuvant for cancer vaccines, whereas back-splice-junction neoantigens offer both vaccine opportunities and tolerance risks. Recent advances in scarless circularization, topology-sensitive purification, dsRNA depletion, and lyophilized formulations have begun to address key manufacturing bottlenecks, although clinical-scale recovery and process scalability remain insufficiently characterized. Key applications include circRNA cancer vaccines, transient CAR-T/NK cell engineering, tumor-suppressor replacement, and circRNA-encoded bispecific T-cell engagers. The field now requires real-time pharmacokinetic tracking, reproducible and scalable manufacturing, validated liquid-biopsy assays, and indication-specific regulatory pathways to translate circRNA from bench to bedside.
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