Hyaluronidase-powered microneedles for significantly enhanced transdermal delivery efficiency.

Microneedles (MNs) with enhanced delivery efficiency have revolutionized the transdermal drug delivery system for treating systemic illness. However, the bioavailability of MNs was still far from the clinical requirements by only overcoming the stratum corneum barrier. Herein, hyaluronidase (HAase)-powered MNs were developed as a top-down permeation-enhancement strategy to hijack the sequential transdermal barriers for improved bioavailability. HAase MNs with robust mechanical strength showed excellent skin penetration ability and significantly enhanced the transdermal delivery efficacy of macromolecular drugs as compared to that of HAase-absent MNs, resulting in considerable effect to subcutaneous injection in terms of biodistribution, bioavailability, and therapeutical efficacy. As evidenced from the distribution of trypan blue and fluorescence underlying skin, the positive effects exerted by HAase MNs could be ascribed to the depolymerization of HA that would loosen the subcutaneous space and destruct the extracellular matrix barrier to promote drug diffusion and permeation in larger area and greater depth. Notably, the transient interconversion of keratin from α-helix to β-sheet that might assist the drug residues on the skin surface permeate across the stratum corneum during administration might be another reason not to be ignored. As a labor-saving strategy, HAase-powered MNs offers a promising and painless administration route for macromolecules.