Fibrotic diseases cause organ failure that lead to ~45% of all deaths in the United States. Activated macrophages stimulate fibrosis by secreting cytokines that induce fibroblasts to synthesize collagen and extracellular matrix proteins. Although suppression of macrophage‐derived cytokine production can halt progression of fibrosis, therapeutic agents that prevent release of these cytokines (e.g., TLR7 agonists) have proven too toxic to administer systemically. Based on the expression of folate receptor β solely on activated myeloid cells, we have created a folate‐targeted TLR7 agonist (FA‐TLR7‐54) that selectively accumulates in profibrotic macrophages and suppresses fibrosis‐inducing cytokine production. We demonstrate that FA‐TLR7‐54 reprograms M2‐like fibrosis‐inducing macrophages into fibrosis‐suppressing macrophages, resulting in dramatic declines in profibrotic cytokine release, hydroxyproline biosynthesis, and collagen deposition, with concomitant increases in alveolar airspaces. Although nontargeted TLR7‐54 is lethal at fibrosis‐suppressing doses, FA‐TLR7‐54 halts fibrosis without evidence of toxicity. Taken together, FA‐TLR7‐54 is shown to constitute a novel and potent approach for treating fibrosis without causing dose‐limiting systemic toxicities. Synopsis A folate‐targeted TLR7 agonist (FA‐TLR7‐54) is shown to alleviate pulmonary fibrosis with no detectable toxicity. Achievement of this outcome is enabled by selective reprogramming of profibrotic to antifibrotic macrophages, suppressing the consequent fibroblast activation and collagen biosynthesis. Folate receptor β (FRβ) is over‐expressed on profibrotic macrophages, allowing folate targeting of TLR7 agonists (FA‐TLR7‐54) specifically to profibrotic macrophages in lungs of bleomycin‐induced fibrotic mice. Upon intravenous treatment with FA‐TLR7‐54, activated macrophages in the fibrotic lungs of bleomycin‐treated mice reprogram from a profibrotic to antifibrotic phenotype, as evidenced by the changes in many molecular markers. Treatment of fibrotic mice with FA‐TLR7‐54 reduces the collagen, hydroxyproline, alpha smooth muscle actin and fibrotic (Ashcroft) scores of affected lungs while improving available air space and alveolar morphology. Therapeutic doses of folate‐targeted FA‐TLR7‐54 cause no detectable toxicities, while nontargeted TLR7‐54 causes prominent systemic inflammation, dramatic animal weight loss, and significantly increased mortality in treated mice.
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