Overcoming Oral Mucosal Barriers: Next-Generation Oromucosal Formulation Strategies for Efficient Therapy of Oral Diseases

Oral mucosal diseases often lead to structural damage and functional impairment due to high recurrence and malignant progression. Current therapeutic outcomes remain unsatisfactory owing to the complex oral microenvironment. Recent reviews have covered individual aspects of oral mucosal drug delivery, such as bioactive materials, mucoadhesive systems, and nanocarriers, but few have considered all four interrelated dimensions, including saliva-mediated adhesive barriers, epithelial permeability, biomechanical adaptability, and translational bottlenecks, in an integrated manner. The present review offers an attempt to consolidate these dimensions into one framework, aiming to provide readers with a more comprehensive perspective on the challenges inherent in this field. To underpin this framework, we conducted a structured literature search covering Web of Science (2015–2026), with predefined inclusion/exclusion criteria, followed by thematic synthesis. We first summarize the clinicopathological features and current treatment landscape of major oral mucosal diseases. We then dissect three critical barriers to transmucosal delivery: adhesive interference by salivary flow, epithelial tight junction resistance, and dynamic biomechanical forces (e.g., chewing, tongue movement). Drawing on saliva and mucosa interfacial physics, we rationalize the need for wet-adhesive material design and survey diverse mucoadhesive polymers and formulations, detailing their binding mechanisms. For epithelial penetration, we highlight design principles of microneedles and nanocarriers while critically discussing their dual-edged safety–efficacy profiles. To cope with the highly deformable oral biomechanical environment, we propose mechanical property matching and asymmetric structural designs. Finally, we outline key translational bottlenecks and future breakthroughs. This review offers an integrated, barrier-informed guide for next-generation oromucosal formulations.