12P - STING-activable pyroptotic nanoparticles deliver GSDMDNT mRNA for in situ pancreatic cancer vaccination and immunotherapy

Background

In situ cancer vaccines are capable of leveraging the immune system to attack tumors by utilizing the whole repertoire of tumor antigens present in the tumor microenvironment. Pyroptosis caused by N-terminal of gasdermin D (GSDMD^NT) could be adopted to extensively release tumor antigens in situ, while its delivery to cancer cells is a major challenge.

Methods

We synthesized a series of highly branched poly(β-amino ester)s (hPBAE) polymers modified with various end caps, identifying a lead hPBAE candidate that possessed satisfactory mRNA translation efficiency and highest immunogenicity via STING agonism. The STING-activating hPBAE (SA-hPBAE) were further condensed with GSDMD^NT mRNA and pancreatic cancer-targeting peptide to construct the STING-Activable and Pyroptotic in situ cancer vaccine (SAPvax).

Results

The STING-stimulating ability of SA-hPBAEwas validated by time- and dose-dependent downstream cytokines (IFN-β, TNF-α, IL-6) production and STING pathway phosphorylation (p-STING, p-TBK1, p-IRF3), which was further supported by dynamic molecular docking of specific end cap and STING protein. The production of SAPvax nanocomplexes was confirmed by electron microscopy. Notably, SAPvax resulted in significant inhibition of pancreatic tumor growth both in vitro and in vivo. A robust synergistic activation of innate and adaptive antitumor immune responses was observed in tumors treated with SAPvax via flow cytometry and transcriptome analysis. SAPvax further exhibited excellent therapeutic effects against tumor recurrence and metastasis via effective induction of memory immunity.

Conclusions

The rational design of current nanocomplexes has proposed a new strategy of in situ cancer vaccine that takes advantages of the cargo GSDMD^NT-mediated pyroptosis and the delivery vector SA-hPBAE-mediated immunostimulatory effects via the STING signaling pathway, promising to provide clinical benefits for patients with pancreatic cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This work was financially supported by the National Natural Science Foundation of China (U20A20378, TB.L.; 82100645, SY.S.).

Disclosure

All authors have declared no conflicts of interest.