Long-acting antiretroviral therapy (LA-ART) holds promise for improving adherence and viral suppression in human immunodeficiency virus (HIV) prevention and treatment, respectively. These LA-ART encompass different delivery modalities such as intravaginal rings, subcutaneous implants, and intramuscular or subcutaneous injectables. However, subcutaneous implants, especially those containing tenofovir alafenamide (TAF), can trigger local inflammation. In this study, we incorporated MCC950, a selective NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inhibitor, into a subcutaneous nanofluidic implant co-delivering TAF and bictegravir (BIC). In a rodent model, MCC950 reduced local inflammation, fibrotic capsule formation, and inflammatory cell infiltration without affecting the antiviral activity of TAF or BIC. Sustained plasma levels of both drugs were maintained for up to 45 days, and imaging mass cytometry and histological analyses confirmed localized immunomodulation. These findings establish inflammasome inhibition as a viable strategy to improve the safety and tolerability of subcutaneous LA-ART and lay the groundwork for future immunomodulatory-enhanced drug delivery systems.