Triple‐Tailored Analgesic Hydrogel System Targeting ADAM17 in Orofacial Inflammatory Pain

Abstract Orofacial inflammatory pain (OFP) is challenging to manage due to its high incidence, complex anatomy, and multifactorial etiology. To address this, a three‐step customized therapeutic system is proposed for prolonged pain relief and efficient local drug delivery. First, ADAM17 is identified as a novel therapeutic target for OFP, and find a small‐molecule inhibitor, TAPI‐1, which can effectively suppress ADAM17 activity. Subsequently, guided by the presence of an amine group on TAPI‐1, an optimized hydrogel matrix is synthesized via Schiff‐base bonding to enable stable encapsulation. The hydrogel, composed of hyaluronic acid derivatives carrying aldehyde (HAALD) and aminated gelatin (AGel), forms a scaffold that slows drug release. Second, for clinical application in orofacial tissue, unmodified hyaluronic acid (HA) and gelatin are incorporated to optimize the hydrogel's rheological properties for practicable injection. Third, to further prolong drug release, customized hollow mesoporous silica nanoparticles are added to trap a portion of TAPI‐1, matching the drug's molecular diameter. This triple‐tailored sustained‐release hydrogel (HHGA hydrogel) maintains effective drug levels for 7 days, aligning with the pain phase and obviously relieving pain in mice. This “drug‐device” innovation exemplifies the potential of personalized medicine in pain management and targeted therapies in translational medicine.