A versatile surface decoration strategy to efficiently encapsulate water‐soluble peptides is developed. By assembling peptide molecules into nanoparticles, diverse physiochemical properties of these compacted molecules are equalized to the surface properties of nanoparticles. Primarily driven by the generic electrostatic attractions, the surface of as‐prepared peptide nanoparticles is decorated with charged amino acids‐grafted poly(lactic‐co‐glycolic acid). This adsorbed polymer layer versatilely blocks the phase transfer of peptide nanoparticles by increasing their affinity to the dispersed phase solvent molecules. Attributed to the ultrahigh encapsulation efficiencies (> 96%), the peptide mass fraction inside the obtained microcomposites is higher than 48%. The plasma calcium level has been efficiently reduced for ≈3 weeks with only one single injection of salmon calcitonin‐encapsulated microcomposite in osteoporotic rats. Similarly, one single injection of exenatide‐encapsulated microcomposites efficiently controls the glycemic level in type 2 diabetic rats for up to 3 weeks. Overall, the developed versatile surface decoration strategy efficiently encapsulates peptides and improves their pharmacokinetic features, regardless of the molecular structure of peptide cargos.

Accuratly controlling drug release from a smart "self-regulated" drug delivery system is still an ongoing challenge. Herein, we developed a surface decoration strategy to achieve an efficient drug encapsulation with precise ratiometric control. Thanks to the surface decoration with cationic carrier materials by electrostatic attraction, the surface properties of different protein and peptide nanoparticles were uniformed to those adsorbed carrier materials. These carrier materials endowed protein and peptide nanoparticles with good dispersity in the oil phase and significantly inhibited the drug transfer from oil to water. With uniform surface properties, we realized the co-encapsulation of multiple types of proteins and peptides with precise ratiometric control. The encapsulation efficiency was higher than 87.8% for insulin. After solidification, the adsorbed materials on the surface of nanoparticles formed a solid protection layer, which prolonged the mean residence time of insulin from 3.3 ± 0.1 h (for insulin solution) to 47.5 ± 1.3 h. In type 1 diabetes, the spermine-modified acetalated dextran microparticle co-loaded with insulin, glucose oxidase and catalase maintained the blood glucose level within the normal range for 7 days.

Microparticles are successfully engineered through controlled interfacial self-assembly of polymers to harmonize ultrahigh drug loading with zero-order release of protein payloads. To address their poor miscibility with carrier materials, protein molecules are transformed into nanoparticles, whose surfaces are covered with polymer molecules. This polymer layer hinders the transfer of cargo nanoparticles from oil to water, achieving superior encapsulation efficiency (up to 99.9%). To control payload release, the polymer density at the oil-water interface is enhanced, forming a compact shell for microparticles. The resultant microparticles can harvest up to 49.9% mass fraction of proteins with zero-order release kinetics in vivo, enabling an efficient glycemic control in type 1 diabetes. Moreover, the precise control of engineering process offered through continuous flow results in high batch-to-batch reproducibility and, ultimately, excellent scale-up feasibility.

A surface adsorption strategy is developed to enable the engineering of microcomposites featured with ultrahigh loading capacity and precise ratiometric control of co-encapsulated peptides. In this strategy, peptide molecules (insulin, exenatide, and bivalirudin) are formulated into nanoparticles and their surface is decorated with carrier polymers. This polymer layer blocks the phase transfer of peptide nanoparticles from oil to water and, consequently, realizes ultrahigh peptide loading degree (up to 78.9%). After surface decoration, all three nanoparticles are expected to exhibit the properties of adsorbed polymer materials, which enables the co-encapsulation of insulin, exenatide, and bivalirudin with a precise ratiometric control. After solidification of this adsorbed polymer layer, the release of peptides is synchronously prolonged. With the help of encapsulation, insulin achieves 8 days of glycemic control in type 1 diabetic rats with one single injection. The co-delivery of insulin and exenatide (1:1) efficiently controls the glycemic level in type 2 diabetic rats for 8 days. Weekly administration of insulin and exenatide co-encapsulated microcomposite effectively reduces the weight gain and glycosylated hemoglobin level in type 2 diabetic rats. The surface adsorption strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performance of peptides, especially for the combination of peptides.

Drug delivery systems with high content of drug can minimize excipients administration, reduce side effects, improve therapeutic efficacy and/or promote patient compliance. However, engineering such systems is extremely challenging, as their loading capacity is inherently limited by the compatibility between drug molecules and carrier materials. To mitigate the drug-carrier compatibility limitation towards therapeutics encapsulation, we developed a sequential solidification strategy. In this strategy, the precisely controlled diffusion of solvents from droplets ensures the fast in-droplet precipitation of drug molecules prior to the solidification of polymer materials. After polymer solidification, a mass of drug nanoparticles is embedded in the polymer matrix, forming a nano-in-micro structured microsphere. All the obtained microspheres exhibit long-term storage stability, controlled release of drug molecules, and most importantly, high mass fraction of therapeutics (21.8–63.1 wt%). Benefiting from their high drug loading degree, the nano-in-micro structured acetalated dextran microspheres deliver a high dose of methylprednisolone (400 μg) within the limited administration volume (10 μL) by one single intrathecal injection. The amount of acetalated dextran used was 1/433 of that of low drug-loaded microspheres. Moreover, the controlled release of methylprednisolone from high drug-loaded microspheres contributes to improved therapeutic efficacy and reduced side effects than low drug-loaded microspheres and free drug in spinal cord injury therapy.