Pathophysiology-Informed Design of Negatively Charged Liposomes for Enhanced Antibiotic Delivery across the Intact Tympanic Membrane in Acute Otitis Media Treatment

Acute otitis media (AOM) is a leading cause of oral antibiotic prescriptions for children in the U.S., often resulting in systemic side effects and contributing to antibiotic resistance. Local delivery of antibiotics across an intact tympanic membrane (TM) to treat the infection in the middle ear is challenging due to the impermeable TM, which blocks most molecules via the outermost stratum corneum layer. Recent research has identified liposomes encapsulating antibiotics as a highly promising approach to overcoming the intact TM during AOM, demonstrating superior delivery efficiency. However, their design principles remain elusive, especially regarding the desirable surface charge. While previous research has identified positive surface charge as being more effective for crossing healthy stratum corneum, this study illustrates the opposite is true during infection. We compared hydrogel formulations containing positively and negatively charged liposomes in terms of their <i>in vitro</i> release, permeation across intact TM <i>ex vivo</i>, <i>in vivo</i> AOM treatment efficacy, and tissue-level biocompatibility using an established chinchilla model. Our results indicate that negatively charged liposomes outperformed positively charged ones, successfully eradicating 100% of AOM cases. We attributed this to interactions between the negatively charged liposomes and the immune response to infection. Specifically, the complement activation, which triggers neutrophils' phagocytosis, is enhanced in response to the negatively charged liposomes. Our findings highlight an opportunity to improve delivery efficiency by considering the pathophysiology more wholistically during the design of drug delivery vehicles.