What question did this study set out to answer?

The aim is to develop an ionizable lipid nanoparticle platform to deliver IL-12 circRNA for lung cancer treatment while minimizing systemic toxicity.

April 5, 2026

Abstract 4042: Tumor-tailored ionizable lipid nanoparticles facilitate IL-12 circular RNA delivery for enhanced lung cancer immunotherapy

Key Points

The aim is to develop an ionizable lipid nanoparticle platform to deliver IL-12 circRNA for lung cancer treatment while minimizing systemic toxicity.
Developed a platform using circular RNA for sustained protein expression.
Screened ionizable lipids using a high-throughput combinatorial method.
Administered lead LNP H1L1A1B3 in lung cancer models via intratumoral and intratracheal routes for evaluation.
Conducted immunological profiling to assess immune cell recruitment in tumor microenvironment.
H1L1A1B3 showed fourfold higher circRNA transfection efficiency compared to ALC-0315.
Intratumoral injection delayed tumor progression and combined with anti-PD-L1 enhanced tumor regression.
Significant increases in CD45+ leukocytes and improved CD8+/Treg ratio observed in immune profiling.
Sustained serum levels of IL-12 and IFN-γ for at least five days post-administration without systemic liver toxicity.

Abstract

Abstract mRNA-based immunotherapies are hindered by systemic toxicity and transient expression, necessitating frequent dosing. This is especially problematic for potent cytokines like Interleukin-12 (IL-12), whose use is limited by severe adverse effects. To address this, we developed a platform using circular RNA (circRNA), which offers more sustained protein expression than linear mRNA. A high-throughput combinatorial method (Ugi reaction) was used to screen for ionizable lipids to deliver circRNA to lung tumors. The lead LNP, H1L1A1B3, showed a fourfold increase in circRNA transfection efficiency over the ALC-0315 standard. H1L1A1B3 LNPs were also dual-functional, acting as an immune adjuvant by potently activating NF-κB and IRF innate immune pathways. This LNP was loaded with circRNA encoding IL-12, providing significantly delayed decay in protein expression. Therapeutic efficacy was validated in two lung cancer models. In a subcutaneous LLC1 model, a single intratumoral injection of H1L1A1B3-circRNA-IL-12 LNPs delayed tumor progression. Combined with an anti-PD-L1 checkpoint inhibitor, this induced robust tumor regression. Immunological profiling revealed a profound remodeling of the tumor microenvironment (TME), including an eightfold increment in CD45+ leukocytes and enhanced infiltration of CD8+ and CD4+ T cells, increasing the CD8+/Treg ratio. Second, in an orthotopic HKP1 NSCLC model, a single intratracheal administration of the IL-12 circRNA LNPs effectively suppressed lung tumor growth. This local delivery resulted in sustained serum IL-12 and IFN-γ for at least five days but did not cause systemic liver toxicity (normal AST/ALT levels). The treatment successfully recruited immune cells, including CD8+ T cells, to the lung tumors. In conclusion, this work presents a tumor-tailored, dual-function LNP (H1L1A1B3) that efficiently delivers stable IL-12 circRNA and provides intrinsic immunostimulatory effects. The platform enables sustained, localized cytokine expression, remodeling the TME to be immunologically "hot." These results highlight the potential of this LNP-circRNA platform to advance RNA drug delivery, offering a potent and safer immunotherapeutic strategy for lung cancer by overcoming systemic toxicity and transient expression hurdles. Citation Format: Yue Xu, Shufen Xu, Bowen Li. Tumor-tailored ionizable lipid nanoparticles facilitate IL-12 circular RNA delivery for enhanced lung cancer immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4042.

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