Upcycling of cardoon root biomass into polyhydroxyalkanoate nanocarriers for docetaxel delivery.

Lignocellulosic residues represent a promising low-cost feedstock for the sustainable production of polyhydroxyalkanoates (PHAs), although their integration into high-value biomedical applications remains limited. This work reports an integrated approach for the valorization of cardoon root biomass into poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) and its subsequent application as a nanocarrier for docetaxel delivery. Cardoon roots were subjected to cascade fractionation followed by deep eutectic solvent (DES)-based pretreatment to enhance lignin removal while preserving the carbohydrate fraction. Among the tested conditions, a choline chloride/lactic acid system (1:4 mol/mol, 140 °C, 3 h) provided the best balance between delignification (≈ 70%) and cellulose retention (≈ 95%), enabling efficient enzymatic saccharification and glucose release (up to 12.8 g L-1). The resulting hydrolysate was directly used as a carbon source for PHBHHx production in an engineered Escherichia coli strain, yielding polymers with high molecular weight (up to 2.1 × 105 g mol-1) and a high hydroxyhexanoate content (∼ 37 mol%), suitable for nanoparticle formulation. PHBHHx nanoparticles were prepared via nanoprecipitation and exhibited controlled size (∼ 220-250 nm), narrow size distribution, and high docetaxel encapsulation efficiency (> 85%). The nanocarriers showed sustained drug release (∼ 45% over 35 days) and good colloidal stability, while in vitro studies on 4 T1 and 3 T3 cells demonstrated time-dependent cell uptake, an enhanced early cytotoxicity compared to free drug and absence of intrinsic toxicity of the unloaded system. Overall, this work demonstrates an integrated cascade for the valorization of aged cardoon-root, from tailored fractionation to PHBHHx formulation into functional drug-delivery material.