Acid-responsive PEGylated branching PLGA nanoparticles integrated into dissolving microneedles enhance local treatment of arthritis

The low drug-loading and permeation enhancement abilities of PLGA nanoparticles limit their use as transdermal delivery vehicles. We recently designed PEGylated star-shaped PLGA, which hybridized with calcium carbonate to form nanoparticles [6 s-NPs (CaCO3)] with immune stealth and acid-responsive properties, which increased the loading of tetrandrine (Tet), a poorly soluble antiarthritis active ingredient, by 3.26-fold compared with that of single-chain PLGA nanoparticles. The 6 s-NPs (CaCO3) resulted in acid-responsive release of more cargo in both in vitro release medium (pH 5.5) and fibroblast-like synoviocytes (FLSs) (p < 0.0001), thereby inducing stronger cytotoxic effects of the loaded Tet on the TNF-α-induced abnormal proliferation of FLSs than Tet-loaded 6 s-NPs (no CaCO3) and Tet aqueous dispersion (Free Tet) (p < 0.0001). However, the number of 6 s-NPs (CaCO3) incorporated by RAW264.7 cells was significantly lower than that of PLGA nanoparticles without PEGylation-endowed immune escape function. Furthermore, the nanoparticles were integrated into peach gum-fabricated dissolving microneedles with higher mechanical hardness and better physical stability than hyaluronic acid-formed microneedles. This integrated delivery strategy dramatically increased synovial uptake of Tet via the transdermal route and was further enhanced by the cofunctionalization with stealth escape from phagocytes and inflammatory acidity-triggered release. The observed improvement in adjuvant-induced arthritis involved stronger regulation of the VEGF, JAK2/p-JAK2, and STAT3/p-STAT3 pathways, which was superior to deleting certain currently designed delivery capacities. This newly fabricated multifunctional transdermal vehicle is therefore a promising therapeutic approach for protecting against local inflammation.