Localized nano-doxycycline platforms for antimicrobial and regenerative oral therapy: A systematic review.

BACKGROUND: Local doxycycline is used in periodontal therapy for antimicrobial and host-modulatory purposes, but conventional systemic and local formulations have limitations related to exposure, retention, release control and application-specific functionality. Nano-enabled systems have been investigated across periodontal, regenerative, implant, endodontic, dentinal, pulpal and oral-mucosal applications. METHODS: PubMed/MEDLINE, Scopus and ScienceDirect were searched for original studies published from 2010 to July 2025. Study eligibility, evidence level, formulation characteristics, dose, drug loading, release, biological outcomes and risk of bias were assessed. Randomized human studies were evaluated using RoB 2, the non-randomized human study using ROBINS-I, animal studies using SYRCLE and laboratory studies using QUIN. Patent records were appraised separately and were not treated as therapeutic evidence. RESULTS: Eligibility reappraisal retained 21 studies: five human, four animal and 12 in-vitro or ex-vivo investigations. Human evidence was limited mainly to adjunctive periodontal-pocket therapy, whereas implant, regenerative, endodontic, dentinal and pulpal applications remained predominantly preclinical. Reported systems included nanogels, PLGA nanospheres, electrospun fibres and membranes, polymersomes, liposomes, nanotubes, implant coatings and mineral carriers. Dimensional characterization was common, but administered dose, measured loading, encapsulation efficiency and standardized release data were inconsistently reported. Formal local or systemic pharmacokinetic parameters were generally absent. Methodological concerns included small samples, incomplete randomization or blinding, limited dose-matched comparators and heterogeneous outcome definitions. Patent reassessment identified an adjacent and partly out-of-scope landscape rather than evidence of commercial readiness. CONCLUSIONS: Localized nano-doxycycline demonstrates formulation feasibility and application-specific biological or early clinical signals, but the evidence does not establish class-wide superiority over conventional doxycycline. Future studies require standardized formulation reporting, local and systemic exposure measurements, dose-matched controls, resistance surveillance, long-term safety, scalable manufacturing and adequately powered clinical trials.