Wound healing, a critical biological process vital for tissue restoration, has spurred a global market exceeding $15 billion for wound care products and $12 billion for scar treatment. Chronic wounds lead to delayed or impaired wound healing. Natural bioactive compounds, prized for minimal side effects, stand out as promising candidates for effective wound healing. In response, researchers are turning to nanotechnology, employing the encapsulation of these agents into drug delivery carriers. Drug delivery system will play a crucial role in enabling targeted delivery of therapeutic agents to promote tissue regeneration and address underlying issues such as inflammation, infection, and impaired angiogenesis in chronic wound healing. Drug delivery carriers offer distinct advantages, exhibiting a substantial ratio of surface area to volume and altered physical and chemical properties. These carriers facilitate sustained and controlled release, proving particularly advantageous for the extended process of wound healing, that typically comprise a diverse range of components, integrating both natural and synthetic polymers. Additionally, they often incorporate bioactive molecules. Despite their properties, including poor solubility, rapid degradation, and limited bioavailability, various natural bioactive agents face challenges in clinical applications. With a global research, emphasis on harnessing nanomaterial for wound healing application, this research overview engages advancing drug delivery technologies to augment the effectiveness of tissue regeneration using bioactive molecules. Recent progress in drug delivery has poised to enhance the therapeutic efficacy of natural compounds in wound healing applications.

Polyphenols, natural compounds rich in phenolic structures, are gaining prominence due to their antioxidant, anti-inflammatory, antibacterial, and anticancer properties, making them valuable in biomedical applications. Through covalent and noncovalent interactions, polyphenols can bind to biomaterials, enhancing their performance and compensating for their shortcomings. Such polyphenol-based biomaterials not only increase the efficacy of polyphenols but also improve drug stability, control release kinetics, and boost the therapeutic effects of drugs. They offer the potential for targeted drug delivery, reducing off-target impacts and enhancing therapeutic outcomes. In tissue engineering, polyphenols promote cell adhesion, proliferation, and differentiation, thus aiding in the formation of functional tissues. Additionally, they offer excellent biocompatibility and mechanical strength, essential in designing scaffolds. This review explores the significant roles of polyphenols in tissue engineering and drug delivery, emphasizing their potential in advancing biomedical research and healthcare.

In normal chronic wound healing pathways, the presence of strong and persistent inflammation states characterized by high Reactive Oxygen Species (ROS) concentrations is one of the major concerns hindering tissue regeneration. The administration of different ROS scavengers has been investigated over the years, but their effectiveness has been strongly limited by their short half-life caused by chronic wound environmental conditions. This work aimed at overcoming this criticism by formulating bioartificial hydrogels able to preserve the functionalities of the encapsulated scavenger (i.e., gallic acid-GA) and expand its therapeutic window. To this purpose, an amphiphilic poly(ether urethane) exposing -NH groups (4.5 × 1020 units/gpolymer) was first synthesized and blended with a low molecular weight hyaluronic acid. The role exerted by the solvent on system gelation mechanism and swelling capability was first studied, evidencing superior thermo-responsiveness for formulations prepared in saline solution compared to double demineralized water (ddH2O). Nevertheless, drug-loaded hydrogels were prepared in ddH2O as the best compromise to preserve GA from degradation while retaining gelation potential. GA was released with a controlled and sustained profile up to 48 h and retained its scavenger capability against hydroxyl, superoxide and 1\'-diphenyl-2-picrylhydrazyl radicals at each tested time point. Moreover, the same GA amounts were able to significantly reduce intracellular ROS concentration upon oxidative stress induction. Lastly, the system was highly cytocompatible according to ISO regulation and GA-enriched extracts did not induce NIH-3T3 morphology changes.

The long quest for efficient drug administration has been looking for a universal carrier that can precisely transport traditional drugs, new genomic and proteic therapeutic agents. Today, researchers have found conditions to overcome the two main drug delivery dilemmas. On the one side, the versatility of the vehicle to efficiently load, protect and transport the drug and then release it at the target place. On the other hand, the questions related to the degree of PEGylation which are needed to avoid nanoparticle (NP) aggregation and opsonization while preventing cellular uptake. The development of different kinds of lipidic drug delivery vehicles and particles has resulted in the development of ionizable lipid nanoparticles (iLNPs), which can overcome most of the typical drug delivery problems. Proof of their success is the late approval and massive administration as the prophylactic vaccine for SARS-CoV-2. These ILNPs are built by electrostatic aggregation of surfactants, the therapeutic agent, and lipids that self-segregate from an aqueous solution, forming nanoparticles stabilized with lipid polymers, such as PEG. These vehicles overcome previous limitations such as low loading and high toxicity, likely thanks to low charge at the working pH and reduced size, and their entry into the cells via endocytosis rather than membrane perforation or fusion, always associated with higher toxicity. We herein revise their primary features, synthetic methods to prepare and characterize them, pharmacokinetic (administration, distribution, metabolization and excretion) aspects, and biodistribution and fate. Owing to their advantages, iLNPs are potential drug delivery systems to improve the management of various diseases and widely available for clinical use.

Nanomedicine has revolutionized the available treatment options during the last decade, but poor selectivity of targeted drug delivery and release is still poses a challenge. In this study, doxorubicin (DOX) and magnetite nanoparticles were encapsulated by freezing-induced loading, coated with polymeric shell bearing two bi-layers of polyarginine/dextran sulphate and finally modified with HER2-specific DARPin proteins. We demonstrated that the enhanced cellular uptake of these nanocarriers predominantly occurs by SKOV-3 (HER2+) cells, in comparison to CHO (HER2-) cells, together with the controlled DOX release using low intensity focused ultrasound (LIFU). In addition, a good ability of DARPin+ capsules to accumulate in the tumor and the possibility of combination therapy with LIFU were demonstrated. A relatively high sensitivity of the obtained nanocarriers to LIFU and their preferential interactions with mitochondria in cancer cells make these carriers promising candidates for cancer treatment, including novel approaches to overcome drug resistance.

Blood-brain barrier (BBB)-permeable middle- or macromolecules (middle/macromolecules) have recently attracted significant attention as new drug delivery carriers into the human brain via receptor-mediated transcytosis (RMT). During the development process of such carriers, it is necessary to thoroughly evaluate their human BBB permeability levels. In such evaluations, our recently established human immortalized cell-based multicellular spheroidal BBB models (hiMCS-BBB models) have shown high potential. However, the specifics of those capabilities have yet to be elucidated. Therefore, in this study, we characterize the ability of the hiMCS-BBB models to evaluate RMT-mediated BBB penetration properties of middle/macromolecules. More specifically, we began by validating transferrin receptor (TfR)-mediated RMT functionalities using transferrin in the hiMCS-BBB models and then examined the BBB permeability levels of MEM189 antibodies (known BBB-permeable anti-TfR antibodies). The obtained results showed that, as with the case of transferrin, temperature-dependent uptake of MEM189 antibodies was observed in the hiMCS-BBB models, and the extent of that uptake increased in a time-dependent manner until reaching a plateau after around 2 h. To further expand the evaluation applicability of the models, we also examined the BBB permeability levels of the recently developed SLS cyclic peptide and observed that peptide uptake was also temperature-dependent. To summarize, our results show that the hiMCS-BBB models possess the ability to evaluate the RMT-mediated BBB-permeable properties of antibodies and peptides and thus have the potential to provide valuable tools for use in the exploration and identification of middle/macromolecules showing excellent BBB permeability levels, thereby contributing powerfully to the development of new drug delivery carriers for transporting drugs into the human brain.

Biodistribution studies are essential in drug carrier design and translation, and radiotracing provides a sensitive quantitation for this purpose. Yet, for biodegradable formulations, small amounts of free-label signal may arise prior to or immediately after injection in animal models, causing potentially confounding biodistribution results. In this study, we refined a method to overcome this obstacle. First, we verified free signal generation in animal samples and then, mimicking it in a controllable setting, we injected mice intravenously with a radiolabeled drug carrier formulation (125I-antibody/3DNA) containing a known amount of free radiolabel (125I), or free 125I alone as a control. Corrected biodistribution data were obtained by separating the free radiolabel from blood and organs postmortem, using trichloroacetic acid precipitation, and subtracting the confounding signal from each tissue measurement. Control free 125I-radiolabel was detected at ≥85% accuracy in blood and tissues, validating the method. It biodistributed very heterogeneously among organs (0.6-39 %ID/g), indicating that any free 125I generated in the body or present in an injected formulation cannot be simply corrected to the free-label fraction in the original preparation, but the free label must be empirically measured in each organ. Application of this method to the biodistribution of 125I-antibody/3DNA, including formulations directed to endothelial target ICAM-1, showed accurate classification of free 125I species in blood and tissues. In addition, this technique rendered data on the in vivo degradation of the traced agents over time. Thus, this is a valuable technique to obtain accurate measurements of biodistribution using 125I and possibly other radiotracers.

Accumulating evidence suggests that exosomes play a key role in Parkinson\'s disease (PD). Exosomes may contribute to the PD progression facilitating the spread of pathological alpha-synuclein or activating immune cells. Glial cells also release exosomes, and transmission of exosomes derived from activated glial cells containing inflammatory mediators may contribute to the propagation of the neuroinflammatory response. Glia-to-neuron transmission of exosomes containing alpha-synuclein may contribute to alpha-synuclein propagation and neurodegeneration. Additionally, miRNAs can be transmitted among cells via exosomes inducing changes in the genetic program of the target cell contributing to PD progression. Exosomes also represent a promising drug delivery system. The brain is a difficult target for drugs of all classes because the blood-brain barrier excludes most macromolecular drugs. One of the major challenges is the development of vehicles for robust delivery to the brain. Targeted exosomes may have the potential for delivering therapeutic agents, including proteins and gene therapy molecules, into the brain. This review summarizes recent advances in the role of exosomes in PD pathology progression and their potential use as drug delivery system for PD treatment, the two faces of the exosomes in PD.

Spherical aerogels are not easily broken during use and are easier to transport and store which can be used as templates for drug delivery. This review summarizes the possible approaches for the preparation of aerogel beads and microspheres based on chitosan and cellulose, an overview to the methods of manufacturing droplets is presented, afterwards, the transition mechanisms from sol to a spherical gel are reviewed in detail followed by different drying processes to obtain spherical aerogels with porous structures. Additionally, a specific focus is given to aerogel beads and microspheres to be regarded as drug delivery carriers. Furthermore, a core/shell architecture of aerogel beads and microspheres for controlled drug release is described and subjected to inspire readers to create novel drug release system. Finally, the conclusions and outlooks of aerogel beads and microspheres for drug delivery are summarized.

Intravesical administration of chemotherapeutic agents can enhance drug accumulation in tumors and reduce systemic side effects. Nanocarriers were developed for intravesical administration and exploit the permeation enhancement effect. In vitro permeation evaluation, the drug transdermal amount and accumulation amounts in the tissue of gemcitabine-loaded nanocarriers through biological membrane significantly increased about 14.8~33.0-fold and 1.5~14.1-fold respectively, when compared to a control group of 1% gemcitabine saline solution. In in vivo intravesical administration, the drug accumulation amount in bladder tissue of nanocarrier of 75.2 ± 5.4 μg was revealed as being comparably higher than that of the control group of 44.8 ± 6.4 μg. In confocal laser scanning microscopy imagery, the penetration depth of fluorescent dyes-rhodamine was increased from 80 μm up to 120 μm when a nanocarrier was used. This result implies that the nanocarrier is a promising drug delivery agent for intravesical administration.