2-Deoxyglucose dendrimer-enabled niclosamide delivery to FRβ-expressing macrophages alleviates endometriosis...

Endometriosis is a chronic, incurable disease. Due to limited efficacy, high recurrence rates, and serious side effects of current treatments, development of new, targeted, non-hormonal therapies is urgently needed. We previously reported that niclosamide, an FDA-approved anthelmintic drug, attenuates endometriotic lesion growth. We further identified folate receptor-β (FRβ)-positive macrophages as contributors to disease progression. Significantly, niclosamide inhibits FRβ⁺ macrophages and reduces inflammation, innervation, and angiogenesis. To develop niclosamide as a non-hormonal and selective immune cell-targeted therapy for endometriosis, we engineered a folic acid-conjugated 2-deoxyglucose dendrimer (FA-2DG-D) using click chemistry to enable selective FRβ-mediated uptake. Conjugation of niclosamide to FA-2DG-D yielded a targeted nanotherapeutic (FA-2DG-D-Niclo) with enhanced aqueous solubility, controlled intracellular release, and excellent batch-to-batch reproducibility. In a mouse model of endometriosis, FA-2DG-D demonstrated lesion-specific accumulation and selective internalization by FRβ⁺ macrophages with minimal off-target organ retention. A single intraperitoneal dose of FA-2DG-D-Niclo (25 or 50 mg/kg/bw of niclosamide) significantly reduced FRβ⁺ macrophage burden, suppressed lesion number and volume, and markedly improved endometriosis-associated hyperalgesia at two weeks post-treatment. Together, these findings establish FRβ⁺ macrophages as a potential target in endometriosis and present FA-2DG-D-Niclo as a non-hormonal, macrophage-focused nanomedicine for precise and effective endometriosis treatment.