Immobilization and Intracellular Delivery of Structurally Nanoengineered Antimicrobial Peptide Polymers Using Polyphenol‐Based Capsules

Abstract Structurally nanoengineered antimicrobial peptide polymers (SNAPPs) are an emerging class of antimicrobials against multidrug‐resistant bacteria. Their encapsulation in particle carriers can improve their therapeutic efficacy by preventing peptide degradation, reducing clearance, and enhancing intracellular delivery and dosage to bacteria‐infected host cells. Herein, two template‐mediated strategies are reported for immobilizing SNAPPs in microcapsules through 1) complexation of SNAPPs with tannic acid (TA) onto porous CaCO 3 templates and subsequent removal of the templates (SNAPP–TA capsules) and 2) adsorption of SNAPPs onto CaCO 3 templates and subsequent encapsulation within a metal–phenolic (Fe III –TA) coating and template removal (SNAPP–Fe III –TA capsules). The loading amounts of SNAPPs are 0.8 and 4.4 pg per SNAPP–TA and SNAPP–Fe III –TA capsule, respectively. At pH 7.4, there is sustained release of SNAPPs, which retain high antimicrobial activity with minimum inhibitory concentration values of ≈30 µg mL −1 in Escherichia coli . Both capsule systems are internalized by alveolar macrophages in vitro, with negligible cytotoxicity and are amenable to nebulization, remaining stable in nebulized droplets. This study demonstrates the potential of engineered polyphenol‐based capsules for peptide drug immobilization and intracellular delivery, which have prospective application in the pulmonary delivery of antimicrobials against respiratory bacterial infections (e.g., pneumonia, tuberculosis).