UCLA

Protein are the most dynamic and diverse macromolecules in living organisms, taking part in almost every biological reaction. While burst progresses have been made in revealing new pathways mediated by proteins and understanding of protein functions, their clinical applications are still limited due to the biological barriers that in vivo protein delivery encounters. Although strategies based on nanoparticles have been introduced to address this problem, failure in overcoming all the barriers simultaneously could lead to the compromised delivery efficacy. Therefore, development of delivery platforms that can effectively overcome those biological barriers comprehensively would help realize their potential into practical applicationsIn this dissertation, novel strategies have been developed for protein delivery based on coacervate nanoreactors or sheddable PMPC conjugated nanocomplexes depending on the target site of protein therapeutics. This dissertation research consists with two topics outlined below:

1. Realize the co-delivery of enzyme cascade to bloodstream. In this part, we combined the strategy of coacervate complex with in situ polymerization to encapsulate enzyme cascade in a coacervate nanoreactor with crosslinked zwitterionic shell. Such structure and surface property enhanced the overall catalytic efficacy, elimination of reaction intermediates, enzymatic stability, and prolonged circulation time of the enzyme cascade, providing a protein delivery platform for enzyme replacement therapy.

2. Realize the systemic delivery of intracellularly functional protein to tumor. In this part, we combined the strategy of “stealth” surface with cell-permeable nanocapsule to construct a nanocomplex with a PMPC shell. The nanocomplex facilitated overcome the biological barriers of immune clearance, tumor accumulation and penetration, cellular internalization, and endosomal escape, displaying an effective tumor inhibition.

Overall, this dissertation utilized various strategies and developed novel protein delivery platforms for overcoming biological barriers and improving the bioavailability of protein therapeutics, which broadens their applications.