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bioRxiv · 10.64898/2026.02.06.704463

Targeted delivery of niclosamide to FRβ-expressing macrophages with engineered 2-deoxy glucose dendrimer alleviates endometriosis progression and associated hyperalgesia

Dhull, A.·Shi, M.·Harvey, M. E.·Page, T. M.·Sharma, R.·Goody, K. J.·Dar, A. I.·Moawad, N. S.·Sirohi, V. K.·Cooke, P. S.·Hayashi, K.·Anjali Sharma, A.
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Abstract

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-{beta} (FR{beta})-positive macrophages as contributors to disease progression. Significantly, niclosamide inhibits FR{beta}+ 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 FR{beta}-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 FR{beta} 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 FR{beta} macrophage burden, suppressed lesion number and volume, and markedly improved endometriosis-associated hyperalgesia at two weeks post-treatment. Together, these findings establish FR{beta} 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. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/704463v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@d0101corg.highwire.dtl.DTLVardef@1d1a0bborg.highwire.dtl.DTLVardef@18f9271org.highwire.dtl.DTLVardef@d76bc7_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Dhull, A., Shi, M., Harvey, M. E., Page, T. M., Sharma, R., Goody, K. J., Dar, A. I., Moawad, N. S., Sirohi, V. K., Cooke, P. S., Hayashi, K., Anjali Sharma, A.. 2026-02-09. Targeted delivery of niclosamide to FRβ-expressing macrophages with engineered 2-deoxy glucose dendrimer alleviates endometriosis progression and associated hyperalgesia. https://doi.org/10.64898/2026.02.06.704463

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