Inhibitory Effect of Lipid Nanoparticle–Encapsulated AtRDR1 on Tumor Cells

Background The RNA-dependent RNA polymerase 1 (RDR1) is a plant-specific protein essential for antiviral defense via RNA silencing. Recent advances in cross-species bioengineering have revealed that the ectopic expression of plant RDR1 in mammalian systems can specifically rescue miRNA deficiencies in cancer cells, thereby inhibiting tumor growth. However, the safe and efficient delivery of heterologous genes remains a challenge. Lipid nanoparticle (LNP) delivery systems have emerged as a promising solution due to their favorable safety profile and efficacy. Results In this study, we optimized the synthesis of LNPs by adjusting key parameters such as the organic-to-aqueous phase ratio, temperature, and buffer composition.Using the optimized conditions, we constructed both pRDR1-LNP and RDR1-mRNA-LNP carriers via microfluidic technology. Subsequently, We demonstrated that these LNPs facilitated the heterologous expression of RDR1, which exerted potent and specific antitumor effects. Furthermore, transcriptomic analysis was employed to elucidate the underlying molecular mechanisms of RDR1-induced tumor suppression. Conclusion Collectively, this work establishes an optimized LNP-based platform for the efficient delivery of RDR1 genetic material. The demonstrated potent and specific antitumor efficacy, coupled with insights into the molecular mechanisms of action, highlights the translational potential of this strategy for cancer therapy and supports its future development, possibly in combination with other treatment modalities.