Asthma is a chronic inflammatory lung disease triggered by a hyperactive immune response to airborne allergens and irritants, resulting in symptoms such as wheezing, coughing, and shortness of breath. Presently, there is no cure for asthma, largely due to its complex and poorly understood mechanisms, including airway remodeling driven by chronic inflammation and multifactorial triggers. Corticosteroids are effective in managing asthma; nonetheless, their prolonged use can lead to serious side effects such as bone loss, weight gain, diabetes, hypertension, skin and eye changes, increased susceptibility to infections, gastrointestinal complications, psychiatric effects, Cushingoid features, and adrenal suppression. Although inhaled corticosteroids are safer alternatives, at high doses or with prolonged use, they can cause growth suppression in children, reduced bone density, skin thinning, cataracts, respiratory infections, and adrenal suppression. To address these difficulties, we propose a novel therapeutic strategy: cell-particle conjugation using mesenchymal stem cells (MSCs) combined with polydopamine-coated, rapamycin-loaded PLGA microspheres (PD-Rapa-MS) to enhance lung-targeted drug delivery and minimize off-target effects. Rapamycin-loaded PLGA microspheres (Rapa-MS) were fabricated and further coated with polydopamine in an alkaline environment. PD-Rapa-MS were then characterized by size distribution, drug loading and encapsulation, release profile, and surface morphology. Further, PD-Rapa-MS were physiologically conjugated with MSCs and assessed for morphology, cytotoxicity, and immunomodulatory activity. PD-Rapa-MS was administered in an asthmatic mouse model to evaluate its therapeutic efficacy, assessed through ELISA and histological analysis. Their particle size (1.85 ± 0.70 µm) and drug loading capacity (1.96 ± 0.08) were characterized using a Multisizer and HPLC analysis, respectively. Furthermore, SEM revealed the spherical shape of the microsphere, while FTIR analysis confirmed the perfect encapsulation of rapamycin within the polymer. Following fabrication, PD-Rapa-MS were conjugated to MSCs and assessed for morphology, viability, and immunomodulatory activity. The results indicated minimal toxicity to MSCs after conjugation. The in vivo results suggest that the conjugated system exerts a synergistic anti-inflammatory effect, likely due to the combined actions of rapamycin and MSCs. This approach enhances the immunosuppressive capabilities of MSCs while leveraging the potent anti-inflammatory properties of rapamycin. Ultimately, this innovative cell-particle platform offers a promising direction for safer, more effective asthma treatment.