(2if) Chemical Conjugation Strategies for Functional Intracellular Delivery of Protein Therapeutics

Protein-based therapeutics comprise a rapidly growing subset of pharmaceuticals, yet the transport of proteins across cell membranes has been a longstanding issue in the field. The potential of proteins as efficacious intracellular therapeutic agents has been highlighted in the use of novel protein scaffolds that inhibit “undruggable” biological targets and more recently by gene-editing machinery for treating human disease. Translating many of these promising technologies for clinically relevant applications requires the development of delivery methods capable of translocating proteins into the cytosol of a cell for functional activity. To this end, I have designed a novel reagent composed of a) anioinic sulfonate moieties, b) lysine-reactive conjugation handle, and 3) self-immolating disulfide linker to provide an “anionic” cloak to protein cargos for enable electrostatic complexation and intracellular delivery with cationic lipid transfection reagents commonly utilized for nucleic acid delivery. I have demonstrated the functional delivery of several different globular protein constructs (including full-length monoclonal antibodies) into cells using both commercial lipid transfection reagents as well as state-of-the-art lipid nanoparticle (LNP) formulations being utilized for in vivo delivery of gene therapies. I envision the use of this strategy as a translational approach for the delivery of many protein therapeutics and secondly as a basic research tool for elucidating the function of full-length proteins within intracellular environments.

Research Interests

My research interests broadly consist of continuing with drug delivery research, particularly the use of LNPs for the development of novel mRNA based therapies. Additionally, I am quite interested in the development of novel drug modalities as a form of cancer immunotherapy as well as engineering protein-based therapies that can be compatible with much of the work I have pursued in my Ph.D.