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

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, siRNA, 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.