Conditional fusogenic lipid nanocarriers for cytosolic delivery of macromolecular therapeutics

Publication Type:

Article

Authors:

Zhong, Q., Tan, E.K., Shyamal, A., Ngambenjawong, C., Parisi, T., Ko, H., Fleming, H.E., Jacks, T., and Bhatia, S.N.

Source:

bioRxiv (2024)

URL:

10.1101/2024.12.27.630514

Abstract:

Macromolecular therapeutics designed for intracellular targets must overcome systemic delivery barriers, target cell membrane impermeability, and inefficient endosomal escape. Here, we engineer a class of conditional fusogenic liposomes (C-FLIPs) that harness the catalytic activity of extracellular proteases present in the pathological microenvironment. This context-specific activation enables on-target membrane fusion with cells in diseased tissue, resulting in cytosolic delivery of therapeutic payloads. We describe the cytoplasmic delivery of three prototypic macromolecular therapeutic classes: peptide degraders, cytotoxic proteins, and ribonucleoprotein particles (RNPs). We further develop C-FLIP to deliver granzyme B (GzmB) to the cytoplasm of cancer cells in vivo and induce pyroptosis in immunologically-inert tumors. Treatment with C-FLIP/GzmB reprograms the immunosuppressive tumor microenvironment and synergizes with checkpoint blockade to result in the regression of established tumors and induce immunological memory. This modular, non-viral, cytosolic delivery platform represents a promising approach to leverage pathological protease activity for targeted delivery of biologics.

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