Bioengineered JMJD3-PROTAC targeted epigenetic immunotherapy strategy for diabetic periodontitis.

Area of Science:

• Biomaterials Science
• Nanotechnology
• Immunology
• Periodontology
• Epigenetics

Background:

• Diabetic periodontitis involves immune dysregulation and impaired tissue repair.
• The nonenzymatic form of JMJD3 contributes to inflammation in diabetic periodontitis.
• Targeted degradation of JMJD3 offers a potential therapeutic strategy.

Purpose of the Study:

• To develop and evaluate a targeted nanotherapeutic system for JMJD3 degradation.
• To restore immune balance and promote tissue repair in diabetic periodontitis.
• To assess the efficacy of the nanoplatform in vitro and in vivo.

Main Methods:

• Engineered a pH/ROS-responsive nanoplatform (P-PLGA@MM) with diselenium-bonded PLGA.
• Loaded the nanoplatform with a JMJD3-targeting PROTAC and camouflaged with macrophage membranes.
• Utilized in vitro and in vivo models of diabetic periodontitis to evaluate the system's performance.

Main Results:

• P-PLGA@MM demonstrated macrophage-specific uptake and efficient intracellular PROTAC release.
• Achieved selective degradation of JMJD3's nonenzymatic activity via the ubiquitin-proteasome pathway.
• In vivo, the nanoplatform promoted collagen regeneration, reduced bone loss, and improved healing without toxicity.

Conclusions:

• Targeted nano-delivery of PROTAC for JMJD3 degradation alleviates inflammation and promotes periodontal regeneration in diabetic periodontitis.
• The P-PLGA@MM system shows potential for localized epigenetic therapy in chronic inflammatory conditions.
• This approach offers a novel strategy for managing diabetic periodontitis and related diseases.