Drug delivery systems (DDSs) represent an emerging focus for many researchers and they are becoming progressively crucial in the development of new treatments. Great attention is given to all the challenges that a drug has to overcome during its journey across barriers and tissues and all the pharmacokinetics modulations that are needed in order to reach the targeting sites. The goal of these pathways is the delivery of drugs in a controlled way, optimizing their bioavailability and minimizing side effects. Recent innovations in DDSs include various nanotechnology-based approaches, such as nanoparticles, nanofibers and micelles, which provide effective targeted delivery and sustained release of therapeutics. In this context, protein-based drug delivery systems are gaining significant attention in the pharmaceutical field due to their potential to revolutionize targeted and efficient drug delivery. As natural biomolecules, proteins offer distinct advantages, including safety, biocompatibility and biodegradability, making them a fascinating alternative to synthetic polymers. Moreover, protein-based carriers, including those derived from gelatin, albumin, collagen, gliadin and silk proteins, demonstrate exceptional stability under physiological conditions, and they allow for controlled and sustained drug release, enhancing therapeutic efficacy. This review provides a comprehensive overview of the current trends, challenges, and future perspectives in protein-based drug delivery, focusing on the types of proteins adopted and the techniques that are being developed to enhance their functionality in terms of drug affinity and targeting capabilities, underscoring their potential to significantly impact modern therapeutics.

Protein-based hydrogels are increasingly recognized as promising biomaterials for advanced drug delivery, owing to their biocompatibility, biodegradability, and ability to recreate extracellular matrix-like environments. By tailoring the protein source, crosslinking strategy, molecular architecture, and functionalization, these hydrogels can be engineered to mimic the mechanical and biological features of native tissues. Protein-derived hydrogels are currently explored across biomedical and pharmaceutical fields, including drug delivery systems, wound healing, tissue engineering, and, notably, cancer therapy. In recent years, growing attention has been directed toward natural protein hydrogels because of their inherent bioactivity and versatile physicochemical properties. This review provides an updated overview of protein-based hydrogel classification, properties, and fabrication methods. It highlights several widely studied natural proteins, such as gelatin, collagen, silk fibroin, soy protein, casein, and whey protein, that can form hydrogels through physical, chemical, or enzymatic crosslinking. These materials offer tunable mechanical behavior, controllable degradation rates, and abundant functional groups that support efficient drug loading and the development of stimuli-responsive platforms. Furthermore, we examine current advances in their application as drug delivery systems, with particular emphasis on cancer treatment. Protein-based hydrogels have demonstrated the ability to protect therapeutic molecules, provide sustained or targeted release, and enhance therapeutic effectiveness. Although critical challenges, such as batch-to-batch variability, sterilization-induced denaturation, and the requirement for comprehensive long-term immunogenicity assessment, must still be addressed to enable successful translation from preclinical studies to clinical application, ongoing advances in the design and functionalization of natural protein hydrogels highlight their promise as next-generation platforms for precision drug delivery.

Background: Targeting Apolipoprotein E4 (ApoE4) represents a frontier in Alzheimer’s disease therapeutics. This study investigates the therapeutic potential of a nutraceutical panel (Polydatin, trans-resveratrol, luteolin, and PEA) by exploring their interaction with the ApoE4 EZ-482 cavity. Methods: Using a dual-platform docking strategy (SwissDock and Schrödinger Maestro) across three structural constructs. Results and Discussion: We identified the full-length protein (1–299) as the optimal target, showing a robust correlation between normalized docking scores (Spearman ρ = 0.79). Crucially, biophysical analysis via dynamic light scattering (DLS) revealed that the ApoE4–oxLDL complex exhibits a ζ-potential of −10.97 mV, a state prone to pathological aggregation. Luteolin and PEA effectively altered this electrostatic environment, inducing significant positive shifts to +2.15 mV and +1.05 mV, respectively. The alignment between computational rankings and experimental ζ-potential perturbations supports the predictive reliability of our model. These findings suggest that nutraceuticals can modulate the ApoE4–oxLDL biophysical profile and highlight that a full structural context is mandatory for developing effective ApoE4-targeted interventions.

Orange processing waste is the largest residue stream of the Mediterranean citrus industry and a concentrated source of pectic polysaccharides and phenolic compounds. Both fractions were recovered from the same residue, and the recovered pectin was evaluated as a wall material for the phenolics. Extraction was carried out by rapid solid–liquid dynamic extraction in a 40 L Naviglio® extractor with water as the only solvent, at 25–27 °C and 10 bar, over fifteen 40 min cycles preceded by a 20 min pre-impregnation, for approximately 10 h in total. Aqueous citrus extracts are rich in ascorbate and reducing sugars, so total phenolic content was determined both directly and after solid-phase clean-up, and only the corrected value is reported as phenolic. Corrected total phenolic content was 312 ± 18 mg GAE/100 g DW against 487 ± 26 mg GAE/100 g DW uncorrected, so non-phenolic reductants accounted for 36.0 % of the raw signal. Radical-scavenging capacity was 21.6 ± 1.4 µmol TE/g DW by DPPH and 48.3 ± 2.9 µmol TE/g DW by ABTS. Hydroxycinnamic acids dominated the chromatographic profile, with flavanone glycosides in the minority, as expected of an aqueous solvent. Pectin recovered from the residue was high-methoxyl at 68.4 ± 1.9 % esterification and was therefore not calcium-reactive as extracted. Enzymatic de-esterification with orange pectin methylesterase gave 38.2 ± 1.6 % with essentially no loss of molecular weight and a blockwise charge distribution (DBabs 19.1 %), whereas an alkali control at matched esterification lost 47 % of its chain length. Continuous-flow gelation of low-methoxyl pectin gave 176 ± 24 nm particles with an encapsulation efficiency of 88.6 ± 2.1 %. The maltodextrin-dried powder retained 71.0 % of its phenolics after 90 days at 25 °C against 22.9 % for the unprotected extract, and intestinal bioaccessibility rose from 31.5 ± 3.6 % to 68.3 ± 4.1 %. The degree of esterification of the recovered pectin determines whether the circular version of the process is chemically available, and is reported here on that basis.