Influence of Nanogel Amphiphilicity on Dermal Delivery: Balancing Surface Hydrophobicity and Network Rigidity

Polymeric nanogels are promising nonirritating nanocarriers for topical delivery applications. However, conventional hydrophilic networks limit encapsulation of hydrophobic therapeutics and hinder tailored interactions with the amphiphilic skin barrier. To address these limitations, we present amphiphilic nanogels containing hydrophilic networks with hydrophobic domains. Two competing factors determine favorable nanogel–skin interactions and need to be balanced through network composition: suitable surface hydrophobicity and low network rigidity (through physical hydrophobic cross-links). To ensure comparability in such investigations, we prepared a library of nanogels with increasing hydrophobic cholesteryl amounts but similar colloidal features. By combining mechanical and surface hydrophobicity tests (atomic force microscopy (AFM)) with dermal delivery experiments on excised human skin, we can correlate an increased delivery efficacy of Nile red to the viable epidermis with a specific network composition, i.e., 20–30 mol % cholesterol. Thus, our nanogel library identifies a specific balance between surface amphiphilicity and network rigidity to guide developments of advanced dermal delivery vehicles.