Abstract 5752: Enhanced cancer therapy strategies utilizing gelatin-lipidoid hybrid nanoparticles for RNA delivery

Abstract Nanoparticle delivery platforms have provided impetus for the emergence of novel RNA-based cancer therapeutics due to their ability to circumvent the physiological and cellular barriers in the delivery. The clinical success of these strategies hinges primarily on the safety and efficacy of the delivery vehicle. Here, we have developed a gelatin-lipidoid hybrid nanoparticle (GLNP) that utilizes gelatin's biocompatibility, biodegradability, and lipidoids' high transfection efficiency. With GLNP, we have demonstrated the efficacy of delivering siRNA and silencing AXL, a receptor tyrosine kinase commonly associated with cancer progression, metastasis, and drug resistance. siRNA is attached to the surface of GLNP through covalent conjugation with gelatin, while the lipidoid on the system's interior electrostatically complexes with the siRNA. siRNAs are well protected by the GLNP when exposed to serum for at least 48 hours. The GLNP's bivalency significantly enhanced the downregulation of target genes in vitro and in vivo. Furthermore, the bivalent GLNP can simultaneously target and downregulate two oncogenes. Apart from siRNA, GLNP was also able to encapsulate and deliver mRNA, thereby suggesting the potential to simultaneously deliver RNA therapeutics to effect knockdown and expression of target proteins and maximize therapeutic effect. The length of the carbon chain of the lipidoid can be manipulated to influence the physico-chemical properties of the GLNP and its efficiency in encapsulating and delivering RNA drugs. Importantly, gelatin was found to effectively shield the cationic lipidoid and negate its toxicity. Toxicity studies indicate that high doses of GLNPs (up to 48 mg/kg BW) are well-tolerated with no significant changes in body weight, hematology, or serum chemistry. The co-administration of GLNP-siAXL and TKI in PDX models has shown notable control of tumor growth. It is important to note that immune checkpoint blockade (ICB) therapy has shown significant survival benefits in NSCLC patients. However, the therapeutic effect is limited to only 20% of patients due to several resistance mechanisms, such as increased expression of oncogenic proteins. Therefore, our future study will explore GLNP's ability to sensitize NSCLC tumors to immune therapy. Citation Format: Abilash Gangula, Dhananjay Suresh, Agasthya Suresh Babu, Zhaohui Li, Anandhi Upendran, Raghuraman Kannan. Enhanced cancer therapy strategies utilizing gelatin-lipidoid hybrid nanoparticles for RNA delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5752.