Search

Scheme 1. Schematic illustration of Persistent immune response: Twice tumor shed induced by sialic acid–modified vincristine sulfate liposomes. (A) Preparation of SA-CH-modified vincristine sulfate liposomes. (B) Schematic illustration of SA-CH-modified vincristine sulfate liposomes, which effectively target tumor-associated macrophages, improve the tumor immunosuppressive microenvironment, and induce anti-tumor immune responses. [Display omitted] Studies have shown that tumor-associated macrophages (TAMs) are crucial for the establishment and maintenance in immunosuppressive tumor immune microenvironment (TIME), which can help tumor cells to achieve immune escape and attenuate antitumor therapy. Siglecs, the receptors of sialic acid (SA), widely exist in TAMs, which could be targeted to disrupt TIME and inhibit tumor growth at the root. Therefore, a SA–modified VCR liposome was reported (VCR-SSAL). Cellular and pharmacodynamic experiments showed that VCR-SSAL exhibited strong TAMs targeting and tumor-killing ability. Interestingly, VCR-SSAL treatment induced a phenomenon in which the cancerous tissues were "fell off" from the growth site, after which the wound gradually healed. Three months after the wound healed, the mice whose tumors fell off were re-inoculated, and the tumor fell off again without treatment, with an exfoliation rate of 100%. We speculated that this special efficacy might be due to that VCR loaded in VCR-SSAL could activate adaptive immunity by inducing DNA damage, promoting cytotoxic T lymphocytes (CTLs) infiltration into tumor sites, and enhancing the antitumor immune response. Thus, this study might provide new insights into the application of traditional chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

mRNA vaccines are attractive prospects for the development of DC-targeted vaccines; however, no clinical success has been realized because, currently, it is difficult to simultaneously achieve DC targeting and efficient endosomal/lysosomal escape. Herein, we developed a sialic acid (SA)-modified mRNA vaccine that simultaneously achieved both. The SA modification promoted DCs uptake of lipid nanoparticles (LNPs) by 2 times, >90% of SA-modified LNPs rapidly escaped from early endosomes (EEs), avoided entering lysosomes, achieved mRNA simultaneously translated in ribosomes distributed in the cytoplasm and endoplasmic reticulum (ER), significantly improved the transfection efficiency of mRNA LNPs in DCs. Additionally, we applied cleavable PEG-lipids in mRNA vaccines for the first time and found this conducive to cellular uptake and DC targeting. In summary, SA-modified mRNA vaccines targeted DCs efficiently, and showed significantly higher EEs/lysosomal escape efficiency (90% vs 50%), superior tumor treatment effect, and lower side effects than commercially formulated mRNA vaccines. The SA-modified mRNA vaccine prepared by microfluidic mixture synchronously realizes DCs targeted and efficient EEs and lysosome escape, activates the immune system to eliminate tumors. [Display omitted] • Simultaneously achieving DC targeting and efficient endosomal/lysosomal escape. • First to apply sialic acid- lipid derivative and cleavable PEG-lipid on mRNA LNPs. • Constructed a new computational model to evaluate the transfection efficiency of mRNA delivery vectors. • SA modification significantly improved the antitumor efficacy of mRNA vaccine, and has fewer side effects. [ABSTRACT FROM AUTHOR]