Multicomponent reaction-based combinatorial chemistry for accelerating the discovery of therapeutic protein and nucleic acid delivery materials

Abstract

Abstract Biopharmaceutical drugs, such as therapeutic proteins and nucleic acids, are gaining prominence in modern medicine, presenting great opportunities for addressing major diseases that are challenging to treat with traditional small-molecule drugs. However, delivering these biomacromolecular drugs to specific intracellular targets remains a significant challenge. Due to the large size and hydrophilicity, biomacromolecules cannot easily permeate across cell membrane, thus requiring the development of carrier materials to enable their effective delivery into cells. Despite this need, the labor-intensive synthesis approach and inefficient structure optimization process significantly hinder the discovery of efficient carrier materials. Recently, multicomponent reaction (MCR)-based combinatorial chemistry has emerged as a powerful solution, enabling the rapid generation of a large materials library for screening and structure-activity optimization. In this perspective, we discuss the design principles of therapeutic protein and nucleic acid delivery materials, summarize recent advances, and propose future directions for using the MCR-based combinatorial chemistry to develop next-generation biomacromolecule delivery systems.