Shooting two hawks with one arrow: manganese-doped mesoporous carriers coordinate STING activation and enhanced mRNA translation for in situ cytokine delivery

Cytokine mRNAs, such as IL-12, hold significant promise for anti-tumor therapy. However, their effective localized delivery and the prevention of off-target translation remain challenging. To address these challenges, we synthesized manganese-doped organic mesoporous carriers for mRNA delivery (PMSMns). The Mn doping in PMSMns not only boosted mRNA expression but also enhanced the immune response. Mechanistically, we verified that PMSMns enhance the translation process by relieving glyceraldehyde 3-phosphate dehydrogenase-mediated translational repression and upregulating the level of phosphorylated ribosomal protein S6. Meanwhile, the immune response was enhanced by activating the stimulator of interferon genes (STING) pathway. Furthermore, effective local delivery of mRNA only in tumors without off-target expression in other organs was also achieved. The PMSMns-IL-12/15-mRNA group exhibited the highest levels of IFN-γ, the greatest infiltration of CD8 + T cells, and the most robust recruitment of NK cells, achieving a potent synergistic antitumor effect. Overall, PMSMns provide a dual benefit: boosting mRNA translation and activating the STING pathway, making them ideally suited for cytokine mRNA-based tumor therapy. • Shooting two hawks with one arrow: doping manganese into mesoporous carriers 1) Enhanced the mRNA translation process through upregulation of p-RPS6 and 2) Effectively activated the STING pathway to boost immune response. • Effectively deliver cytokine mRNA in tumors without off-target translation in other organs. • Combining IL-12/IL-15 mRNA therapy with immune checkpoint inhibitors resulted in potent anti-tumor immunotherapy.