The advancement of message RNA (mRNA) -based immunotherapies for cancer is highly dependent on the effective delivery of RNA (Ribonucleic) payloads using ionizable lipid nanoparticles (LNPs). However, the clinical application of these therapies is hindered by variable mRNA expression among different cancer types and the risk of systemic toxicity. The transient expression profile of mRNA further complicates this issue, necessitating frequent dosing and thus increasing the potential for adverse effects. Addressing these challenges, a high-throughput combinatorial method is utilized to synthesize and screen LNPs that efficiently deliver circular RNA (circRNA) to lung tumors. The lead LNP, H1L1A1B3, demonstrates a fourfold increase in circRNA transfection efficiency in lung cancer cells over ALC-0315, the industry-standard LNPs, while providing potent immune activation. A single intratumoral injection of H1L1A1B3 LNPs, loaded with circRNA encoding interleukin-12 (IL-12), induces a robust immune response in a Lewis lung carcinoma model, leading to marked tumor regression. Immunological profiling of treated tumors reveals substantial increments in CD45⁺ leukocytes and enhances infiltration of CD8⁺ T cells, underscoring the ability of H1L1A1B3 LNPs to modulate the tumor microenvironment favorably. These results highlight the potential of tailored LNP platforms to advance RNA drug delivery for cancer therapy, broadening the prospects for RNA immunotherapeutics.

中文翻译：

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肿瘤定制的可电离脂质纳米颗粒促进 IL-12 环状 RNA 递送，增强肺癌免疫治疗

基于信息 RNA (mRNA) 的癌症免疫疗法的进展高度依赖于使用可电离脂质纳米颗粒 (LNP) 有效递送 RNA（核糖核酸）有效负载。然而，这些疗法的临床应用受到不同癌症类型之间mRNA表达的差异以及全身毒性风险的阻碍。 mRNA 的瞬时表达谱使这个问题进一步复杂化，需要频繁给药，从而增加了不良反应的可能性。为了解决这些挑战，采用高通量组合方法来合成和筛选能够有效地将环状 RNA (circRNA) 递送至肺部肿瘤的 LNP。主要 LNP H1L1A1B3 在肺癌细胞中的 circRNA 转染效率比行业标准 LNP ALC-0315 提高了四倍，同时提供有效的免疫激活。单次瘤内注射 H1L1A1B3 LNP（载有编码白细胞介素 12 (IL-12) 的 circRNA）可在 Lewis 肺癌模型中诱导强烈的免疫反应，从而导致肿瘤显着消退。治疗肿瘤的免疫学分析显示 CD45 ⁺白细胞大幅增加，CD8 ⁺ T 细胞浸润增强，强调了 H1L1A1B3 LNP 有利地调节肿瘤微环境的能力。这些结果凸显了定制的 LNP 平台在促进癌症治疗的 RNA 药物输送方面的潜力，拓宽了 RNA 免疫治疗的前景。