Zwitterionic lipid nanoparticles for efficient siRNA delivery and hypercholesterolemia therapy with rational charge self-transformation

<b>Rationale:</b> Effective delivery of small interfering RNA (siRNA) remains a significant challenge in treating hypercholesterolemia due to biocompatibility, cellular uptake, and endosomal escape issues. Rational regulation of carrier surface charge contributes to efficient siRNA delivery <i>in vivo</i>. <b>Methods:</b> This study introduces zwitterionic lipid nanoparticles (ZwiLNPs) as a novel solution to these challenges. By leveraging the unique properties of zwitterionic polymers, we achieved robust siRNA encapsulation and targeted delivery. The design of ZwiLNPs facilitates charge self-transformation in response to physiological conditions, which enhances their biocompatibility and cellular uptake efficiency. <b>Result:</b> <i>In vivo</i> studies demonstrated significant liver-targeting capabilities of ZwiLNPs, with improved endosomal escape following cellular internalization. Comparative analyses confirmed that ZwiLNPs outperform conventional lipid nanoparticles in terms of both cellular uptake and endosomal release. <b>Conclusion:</b> These findings position ZwiLNPs as a promising platform for RNA interference therapies, particularly for hypercholesterolemia and other lipid-related disorders.