Zn-Dipicolylamine-Based ROS-Responsive Bola-Lipid Nanoparticles for Efficient Protein Delivery and Tumor Immunotherapy

In recent years, remarkable progress has been made in cancer immunotherapy. Lipid nanoparticles (LNPs) may serve as an ideal platform for antigen delivery since the lipid structure may be rationally designed and altered to provide the LNPs with specific properties. In this study, a series of ROS-sensitive cationic bola-lipids n -TDZn, in which Zn-DPA was introduced as a hydrophilic headgroup to enhance protein binding, were designed and synthesized. The length of hydrophobic linkage might have effect on the physical properties of the formed LNPs such as particle size and surface potential. The nanosized lipoplex formed from 14-TDZn with the smallest particle size and highest positive potential could induce higher cellular uptake. β-Galactosidase (β-Gal) assay showed that the lipoplexes could efficiently deliver protein into the cells without the loss of protein activity. Subsequent antigen delivery by the lipoplexes demonstrated that the 14-TDZn /OVA lipoplex could well mediate cell internalization and promote the maturation and antigen presentation of bone marrow-derived dendritic cells (BMDCs). Further, in vivo antitumor assays exhibited that 14-TDZn /OVA lipoplex could effectively inhibit tumor growth and enhance T-cell infiltration in tumor tissues, suggesting the activation of the immune system. These results provide a candidate for efficient antigen protein delivery and tumor vaccines.