Polypeptide-based multilayer capsules with anti-inflammatory properties: exploring different strategies to incorporate hydrophobic drugs

More than 90% of drug candidates used in the drug development pipeline and about 40% of drugs on the market are poorly soluble in water based on the definition of the biopharmaceutical classification system. The advent of drug delivery approaches has represented a striking tool to overcome the challenges associated with the use of hydrophobic drugs, such as their low bioavailability and off-target effects. Drug carrier formulations composed of biodegradable and biocompatible polymers, such as polypeptides, have been explored as platforms to host poorly water-soluble drugs to prolong drug circulation, enhance their safety, reduce their immunogenicity, and promote their controlled release. In this work, we evaluated three strategies-co-precipitation, post-encapsulation, and conjugation-to incorporate a hydrophobic model drug, <i>i.e.</i>, curcumin (CUR), into biodegradable multilayer capsules fabricated <i>via</i> a layer-by-layer (LbL) approach. Poly(L-lysine) (PLys) and poly(L-glutamic acid) (PGlu) were adopted as building blocks and alternately assembled onto calcium carbonate (CaCO₃) microparticles to build a polypeptide-multilayer membrane, which acted as a barrier to control the release of the drug. The application of our three formulations in <i>in vitro</i> inflammatory models of THP-1 derived human macrophages and murine microglia showed a reduction of the inflammation with the suppression of three pivotal pro-inflammatory cytokines (<i>i.e.</i>, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α). Moreover, the intracellular release of CUR detected upon uptake studies on activated microglia suggested that our systems could represent a potential therapeutic approach to reduce acute neuroinflammation and modulate microglia phenotype.