Biodegradable Hydrogen-Bonded Organic Framework for Cytosolic Protein Delivery

Hydrogen-bonded organic frameworks (HOFs) are a novel class of porous nanomaterials that show great potential for intracellular delivery of protein therapeutics. However, the inherent challenges in interfacing protein with HOFs, and the need for spatiotemporally controlling the release of protein within cells, have constrained their therapeutic potential. In this study, we report novel biodegradable hydrogen-bonded organic frameworks, termed DS-HOFs, specially designed for the cytosolic delivery of protein therapeutics in cancer cells. The synthesis of DS-HOFs involves the self-assembly of 4-[tris(4-carbamimidoylphenyl) methyl] benzenecarboximidamide (TAM) and 4,4'-dithiobisbenzoic acid (DTBA), governed by intermolecular hydrogen-bonding interactions. DS-HOFs exhibit high efficiency in encapsulating a diverse range of protein cargos, underpinned by the hydrogen-bonding interactions between the protein residue and DS-HOF subcomponents. Notably, DS-HOFs are selectively degraded in cancer cells triggered by the distinct intracellular reductive microenvironments, enabling an enhanced and selective release of protein inside cancer cells. Additionally, we demonstrate that the efficient delivery of bacterial effector protein DUF5 using DS-HOFs depletes the mutant RAS in cancer cells to prohibit tumor cell growth both in vitro and in vivo. The design of biodegradable HOFs for cytosolic protein delivery provides a powerful and promising strategy to expand the therapeutic potential of proteins for cancer therapy.