Glycerol-mediated nose-to-brain codelivery of anti-IL-17 and anti-CD73 antibodies enhances immunotherapy for melanoma brain metastases.

Abstract

Immune checkpoint inhibitors show promise in the treatment of melanoma brain metastases but are limited by CD73/adenosine axis-mediated immune evasion. Directly targeting CD73 with antibodies faces challenges due to poor blood-brain barrier permeability and metabolic regulators within the tumor microenvironment (IL-17-driven HIF-1α/VEGF-A). To overcome these barriers, we developed a nose-to-brain delivery platform using glycerol as a mucosal penetration enhancer to codeliver anti-IL-17 and anti-CD73 antibodies. Glycerol reversibly opened nasal epithelial tight junction proteins, enhancing the brain delivery of anti-IL-17 and anti-CD73 antibodies by 19.4- and 17.1-fold, respectively, while minimizing systemic exposure. Critically, anti-IL-17 attenuated CD73/adenosine axis-mediated immune evasion, significantly boosting anti-CD73 targeting efficacy. Ultimately, this combination promoted CD8⁺ T cell activation and residency, pro-inflammatory macrophage polarization, and reduced T_reg cell infiltration, thereby eliciting a strong antitumor effect. Our results establish an efficient nose-to-brain delivery platform for macromolecules and propose a therapeutic strategy for tumors using anti-IL-17 to overcome TME-imposed limitations in CD73-targeted immunotherapy.