OBJECTIVE: This study evaluated the clinical, microbiological, and immunological results of poly lactic-co-glycolic acid (PLGA) nanospheres containing 20% doxycycline (DOXY) in the treatment of type-2 diabetic patients (DM-2) with chronic periodontitis (CP). MATERIAL AND METHODS: A parallel, double-blind, randomized, placebo-controlled clinical trial was conducted in DM-2 presenting severe and generalized CP. All patients received one-stage full-mouth ultrasonic debridement (FMUD) and they were randomly divided into two groups: PLAC (n = 20)-local application of placebo PLGA nanospheres, and DOXY (n = 20)-local application of doxycycline-loaded nanospheres; both in six non-contiguous sites. Clinical, metabolic (fasting plasma glucose level-FPG and glycated hemoglobin-HbA1c), cytokine pattern (multiplexed bead immunoassay) and microbiological assessments were performed at baseline, and 1, 3, and 6 months after treatment. RESULTS: Both groups showed clinical improvement in all parameters after treatment (p < 0.05). Deep pockets showed improvements in bleeding on probing-BoP (3 and 6 months), PD (at 3 months), and CAL gain (at 1 and 3 months) favoring DOXY (p < 0.05). The percentage of sites presenting PD reduction and CAL gain ≥ 2 mm was higher in DOXY at 3 months (p < 0.05). DOXY group exhibited a significant increase in the levels of anti-inflammatory interleukin (IL)-10 and a reduction in IL-8, IFN-y, IL-6, and IL-17 (p < 0.05), significant reduction in periodontal pathogens (p < 0.05), and a lower mean percentage of HbA1C at 3 months (p < 0.05). CONCLUSION: DOXY nanospheres may be considered a potential adjunct to mechanical debridement in the therapy of periodontitis in DM-2, offering additional benefits in deep pockets, improving the cytokine profile, and reducing periodontal pathogen levels. CLINICAL RELEVANCE: The use of locally applied doxycycline nanospheres may represent an adjunctive therapeutic approach in the treatment of periodontal disease in type-2 diabetic patients, achieving additional benefits in the local modulation of cytokines, microbial reduction, and clinical parameters, especially in deep pockets.