Jigsaw Puzzle-Designed Polyphenol-Macromolecular Supramolecular Networks for Noninvasive Therapy of Deep-Tissue Oral Disease.

Abstract

Transmucosal delivery of macromolecular biopharmaceuticals is favored for being noninvasive and bypassing first-pass metabolism. The oral mucosa provides a convenient route for patient-self-applied drug delivery, but its tight junctions and enzymatic environment hinder drug penetration. Here, we present a noninvasive nanoplatform based on a jigsaw puzzle design, enabling the construction of polyphenol-macromolecule supramolecular networks within ionic liquid (PMIL). Experimental and calculational analyses confirm that leveraging the multiple noncovalent interaction capabilities of green tea polyphenol (epigallocatechin gallate, EGCG), various macromolecular biopharmaceuticals (plasmids, <i>siRNA</i>, proteins, and polypeptides) can be self-assembled into PMIL nanoarchitectures. In periodontitis models, PMIL-loaded teriparatide demonstrated an exceptional tissue penetration capability, simultaneously reducing inflammation and promoting bone regeneration. PMIL enriched commensal and probiotic microbes unrelated to periodontal pathogenesis. Mechanistically, PMIL might modulate PI3K-Akt signaling to simultaneously reduce inflammation and promote bone regeneration. Our ingestible, modular platform provides a noninvasive solution for oral diseases and could be adapted for other macromolecular therapies.