Plugging the Leak of Nanoparticles by Interfacial Polymer Adsorption Enables an Efficient Protein and Peptide Encapsulation

Abstract Encapsulation is a promising technology to enhance the pharmacokinetic properties of proteins and peptides, particularly addressing their short half‐life. Despite its potential, this method has limitations, such as low encapsulation efficiency, a minimal mass fraction of therapeutic agents, and the potential loss of biological activity. In this study, the pivotal role of amphiphilic polymers in achieving efficient protein and peptide encapsulation is delved into. It is found that these polymers not only improve the solvation of cargo nanoparticles but also form a robust 3D polymer layer at the oil/water interface. This interfacial polymer barrier effectively minimizes the escape of proteins and peptides during the encapsulation process, achieving an impressive encapsulation efficiency of up to 99.8% for agents. Remarkably, the mass fraction of these therapeutic agents in the resultant microparticles exceed 59.9 wt.%. The microparticles prolonged payload release for 30 days both in vitro and in vivo, leading to heightened therapeutic efficacy in type 2 diabetic rats. Furthermore, the required amount of polymer for administration is reduced by a factor of 47.5, substantially mitigating inflammatory response at the injection site. In conclusion, the findings highlight the transformative potential of using interfacial polymer accumulation to encapsulate proteins and peptides.