Strategies for overcoming protein and peptide instability in biodegradable drug delivery systems

The global pharmaceutical market has recently shifted its focus from small molecule drugs to peptide, protein, and nucleic acid drugs, which now comprise a majority of the top-selling pharmaceutical products on the market. Although these biologics often offer improved drug specificity, new mechanisms of action, and/or enhanced efficacy, they also present new challenges, including an increased potential for degradation and a need for frequent administration via more invasive administration routes, which can limit patient access, patient adherence, and ultimately the clinical impact of these drugs. Controlled-release systems have the potential to mitigate these challenges by offering superior control over in vivo drug levels, localizing these drugs to tissues of interest (e.g., tumors), and reducing administration frequency. Unfortunately, adapting controlled-release devices to release biologics has proven difficult due to the poor stability of biologics. In this review, we summarize the current state of controlled-release peptides and proteins, discuss existing techniques used to stabilize these drugs through encapsulation, storage, and in vivo release, and provide perspective on the most promising opportunities for the clinical translation of controlled-release peptides and proteins.