Nanodelivery Systems as Innovative Approaches to Modulate Macrophage Polarization in Oral Inflammatory Diseases and Oral Cancer

Oral inflammatory diseases and oral cancer are multifactorial pathologies that share common underlying mechanisms, including oral dysbiosis, chronic inflammation and alterations of the immune response. Macrophage polarization represents the key link between these conditions, with crucial implications in disease progression and therapeutic outcome. In periodontitis, overactive M1 pro-inflammatory macrophages maintain persistent inflammation leading to periodontal tissue breakdown, whereas the M2-like cells are anti-inflammatory and facilitate inflammation resolution and tissue healing. Conversely, in oral squamous cell carcinoma, dominant M2-like tumor associated macrophages suppress anti-cancer immunity and promote aggressive tumor progression, metastasis and recurrence. These contrasting roles of macrophages highlight the importance of novel therapeutic approaches aiming at disease-dependent modulation of macrophage polarization. The therapeutic application of nanovehicles loaded with macrophage-polarizing agents offers significant benefits due to their capacity to overcome the barriers imposed by the specific anatomical characteristics of the oral cavity, while optimizing the pharmacokinetic and stability parameters of therapeutic agents that modulate M1/M2 activation pathways. Functionalizing nanosystems with moieties responsive to the pathological microenvironment—or capable of active molecular targeting—combined with mucoadhesive application or intra-tumoral injection, ensures increased bioavailability of active molecules. This targeted approach maximizes therapeutic efficacy while avoiding exposure of healthy tissues. Optimizing formulation technologies to yield nanosystems tailored to the specific features of a pathology and to immunomodulatory strategies can provide high-efficiency, sustained-release platforms for restoring the physiological parameters of oral tissues. This narrative review summarizes the implication of macrophage phenotypes in periodontitis and oral squamous cell carcinoma and discusses novel nanodelivery systems as immunomodulatory therapeutic approaches.