Enhancing Round Window Membrane Permeability for Inner Ear Drug Delivery: A Systematic Review

Sensorineural hearing loss is a major public health concern, yet its treatment remains limited by the anatomical complexity and biological barriers protecting the cochlea. Among these, the round window membrane (RWM) constitutes a key interface for local drug delivery to the inner ear. However, passive diffusion via intratympanic injection is often insufficient, particularly for hydrophilic, large, or negatively charged molecules such as gene therapy vectors. This systematic review aimed to evaluate biomechanical and biochemical strategies to enhance RWM permeability for more efficient and targeted drug delivery to the inner ear, including direct permeability modulation of the RWM properties or indirect enhancement mechanisms increasing drug delivery without altering intrinsic membrane permeability. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a comprehensive literature search was conducted using the Scopus, MEDLINE/PubMed, Cochrane, and CINAHL electronic databases. In vivo studies and clinical trials involving biochemical or biomechanical strategies to enhance RWM permeability were included. Risk of bias was assessed using the SYRCLE (Systematic Review Center for Laboratory Animal Experimentation) tool. Out of 1776 screened articles, 89 met the inclusion criteria. Four biochemical approaches and three biomechanical strategies were identified, respectively: (1) hydrogels, thermogels, and emulsions, (2) nanosystems, (3) microsystems, and (4) permeabilizers, and (1') sonoporation, (2') acoustic stimulation, and (3') magnetic systems. Most studies reported improved drug delivery to the inner ear or therapeutic efficacy. While earlier research focused on hydrogels, thermogels, emulsions, permeabilizers, and acoustic stimulation for small molecules such as corticoids and antioxidants, recent studies increasingly explore nanosystems, microsystems, sonoporation, and magnetic methods to facilitate the delivery of larger agents, including gene therapy. This review also highlights that while many strategies are already available and effective in animal models, further research is essential to facilitate the clinical translation of both existing and emerging delivery methods.