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Article révisé par les pairs
Résumé : Nanobodies are emerging as attractive biopharmaceuticals due to their small size, stability and target specificity. However, their therapeutic use has largely been restricted to extracellular targets because of a lack of efficient delivery methods. This limitation is particularly relevant for diseases caused by dysfunctional intracellular proteins, such as cystic fibrosis. Here we show that cell-permeable nanobodies can modulate an intracellular disease-relevant target: the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel carrying the common F508del mutation. By combining a CFTR-binding nanobody with cell-penetrating peptides, we achieved intracellular delivery in cystic fibrosis bronchial epithelial cells. The delivered nanobody stabilizes misfolded F508del-CFTR, promotes its maturation and trafficking to the apical membrane and restores chloride channel activity. Moreover, the cell-permeable nanobody enhances the efficacy of approved CFTR modulator drug combination in primary airway epithelial cultures from patients with cystic fibrosis. These findings establish cell-permeable nanobodies as promising biopharmaceuticals for intracellular protein targeting and therapeutic modulation. (Figure presented.)

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