Site specific oral delivery of many biopharmaceutical classification system (BCS) class II and IV drugs is challenging due to their poor solubility, low permeability and degradation in the gastrointestinal tract. Whilst colloidal carriers have been used to improve the bioavailability of such drugs, most nanocarriers based drug delivery systems suffer from multiple disadvantages, including low encapsulation efficiency (liposomes, polymeric nanoparticles), complex synthesis methods (silica, silicon-based materials) and poorly understood biodegradability (inorganic nanoparticles). Herein, a novel pH responsive nanocolloids were self-assembled using natural compounds such as bovine beta-lactoglobulin (BLG) and succinylated beta-lactoglobulin (succ. BLG) cross-linked with epsilon poly L-lysine (BCEP and BCP), and found to possess high loading capacity, high aqueous solubility and site-specific oral delivery of a poorly soluble nutraceutical (curcumin), improving its physicochemical properties and biological activity in-vitro and ex-vivo. Our optimized synthesis formed colloids of around 200 nm which were capable of encapsulating curcumin with similar to 100% encapsulation efficiency and similar to 10% w/w drug loading. By forming nanocomplexes of curcumin with BLG and succ. BLG, the aqueous solubility of curcumin was markedly increased by similar to 160-fold and similar to 86-fold, respectively. Encapsulation with BLG increased the solubility, whereas succ. BLG prevent release of encapsulated curcumin when subjected to gastric fluids as it is resistant to breakdown on exposure to pepsin at acidic pH. In conditions mimicking the small intestine, Succ. BLG was more soluble resulting in sustained release of the encapsulated drug at pH 7.4. Additionally, crosslinking succ. BLG with E-PLL significantly enhanced curcumin's permeability in an in-vitro Caco-2 cell monolayer model compared to curcumin solution (dissolved in 1% DMSO), or non-crosslinked BLG/succ. and BLG. In a mouse-derived intestinal epithelial 3D organoid culture stimulated with IL-1 beta, BLG-CUR and crosslinked BCEP nanoparticles reduced the production of inflammatory cytokines and chemokines such as Tuf alpha and Cxcl10 more than curcumin solution or suspension while these nanoparticles were non-toxic to organoids. Overall this work demonstrates the promise of nutraceutical-based hybrid self-assembled colloidal system to protect hydrophobic drugs from harsh gastrointestinal conditions and improve their solubility, dissolution, permeability and biological activity. (C) 2020 Elsevier Inc. All rights reserved.