Advancements in nanoscale delivery systems: optimizing intermolecular interactions for superior drug encapsulation and precision release.

Nanoscale preparations, such as nanoparticles, micelles, and liposomes, are increasingly recognized in pharmaceutical technology for their high capability in tailoring the pharmacokinetics of the encapsulated drug within the body. These preparations have great potential in extending drug half-life, reducing dosing frequency, mitigating drug side effects, and enhancing drug efficacy. Consequently, nanoscale preparations offer promising prospects for the treatment of metabolic disorders, malignant tumors, and various chronic diseases. Nevertheless, the complete clinical potential of nanoscale preparations remains untapped due to the challenges associated with low drug loading degrees and insufficient control over drug release. In this review, we comprehensively summarize the vital role of intermolecular interactions in enhancing encapsulation and controlling drug release within nanoscale delivery systems. Our analysis critically evaluates the characteristics of common intermolecular interactions and elucidates the techniques employed to assess them. Moreover, we highlight the significant potential of intermolecular interactions in clinical translation, particularly in the screening and optimization of preparation prescriptions. By attaining a deeper understanding of intermolecular interaction properties and mechanisms, we can adopt a more rational approach to designing drug carriers, leading to substantial advancements in the application and clinical transformation of nanoscale preparations. Moving forward, continued research in this field offers exciting prospects for unlocking the full clinical potential of nanoscale preparations and revolutionizing the field of drug delivery.

Transferability evaluation of the deep potential model for simulating water-graphene confined system.

Machine learning potentials (MLPs) are poised to combine the accuracy of ab initio predictions with the computational efficiency of classical molecular dynamics (MD) simulation. While great progress has been made over the last two decades in developing MLPs, there is still much to be done to evaluate their model transferability and facilitate their development. In this work, we construct two deep potential (DP) models for liquid water near graphene surfaces, Model S and Model F, with the latter having more training data. A concurrent learning algorithm (DP-GEN) is adopted to explore the configurational space beyond the scope of conventional ab initio MD simulation. By examining the performance of Model S, we find that an accurate prediction of atomic force does not imply an accurate prediction of system energy. The deviation from the relative atomic force alone is insufficient to assess the accuracy of the DP models. Based on the performance of Model F, we propose that the relative magnitude of the model deviation and the corresponding root-mean-square error of the original test dataset, including energy and atomic force, can serve as an indicator for evaluating the accuracy of the model prediction for a given structure, which is particularly applicable for large systems where density functional theory calculations are infeasible. In addition to the prediction accuracy of the model described above, we also briefly discuss simulation stability and its relationship to the former. Both are important aspects in assessing the transferability of the MLP model.

Nanoparticle surface decoration mediated efficient protein and peptide co-encapsulation with precise ratiometric control for self-regulated drug release.

Accuratly controlling drug release from a smart "self-regulated" drug delivery system is still an ongoing challenge. Herein, we developed a surface decoration strategy to achieve an efficient drug encapsulation with precise ratiometric control. Thanks to the surface decoration with cationic carrier materials by electrostatic attraction, the surface properties of different protein and peptide nanoparticles were uniformed to those adsorbed carrier materials. These carrier materials endowed protein and peptide nanoparticles with good dispersity in the oil phase and significantly inhibited the drug transfer from oil to water. With uniform surface properties, we realized the co-encapsulation of multiple types of proteins and peptides with precise ratiometric control. The encapsulation efficiency was higher than 87.8% for insulin. After solidification, the adsorbed materials on the surface of nanoparticles formed a solid protection layer, which prolonged the mean residence time of insulin from 3.3 ± 0.1 h (for insulin solution) to 47.5 ± 1.3 h. In type 1 diabetes, the spermine-modified acetalated dextran microparticle co-loaded with insulin, glucose oxidase and catalase maintained the blood glucose level within the normal range for 7 days.

Controlled Interfacial Polymer Self-Assembly Coordinates Ultrahigh Drug Loading and Zero-Order Release in Particles Prepared under Continuous Flow.

Microparticles are successfully engineered through controlled interfacial self-assembly of polymers to harmonize ultrahigh drug loading with zero-order release of protein payloads. To address their poor miscibility with carrier materials, protein molecules are transformed into nanoparticles, whose surfaces are covered with polymer molecules. This polymer layer hinders the transfer of cargo nanoparticles from oil to water, achieving superior encapsulation efficiency (up to 99.9%). To control payload release, the polymer density at the oil-water interface is enhanced, forming a compact shell for microparticles. The resultant microparticles can harvest up to 49.9% mass fraction of proteins with zero-order release kinetics in vivo, enabling an efficient glycemic control in type 1 diabetes. Moreover, the precise control of engineering process offered through continuous flow results in high batch-to-batch reproducibility and, ultimately, excellent scale-up feasibility.

Ab Initio Molecular Dynamics Simulation of Water Transport through Short Carbon Nanotubes.

Water transport through short single-walled (6, 6) carbon nanotubes (CNTs) was investigated with ab initio molecular dynamics (AIMD) simulation at different temperatures. The water molecules under extreme confinement present a one-dimensional jagged pattern owing to hydrogen bonding, with the near-perfect alignment of the dipole orientations. CNTs ending with dangling bonds can promote water dissociation near the entrance and the occurrence of dipole flipping along the water wire at high temperatures, accompanied by the formation of D defects and L defects in the hydrogen-bond network. In contrast, dissociation of water molecules rarely takes place if the dangling bonds at the ends of the CNTs are terminated with H atoms. Angular jumps of water molecules are commonplace inside the narrow CNTs, implying a low-energy barrier for hydrogen-bond exchange among water molecules in narrow CNTs. The simulation results demonstrate the high activity of dangling bonds at the ends of short CNTs, accompanying passivation processes and their profound impact on water structure and transport, which is important for diverse technological applications.

Colloidal Jamming by Interfacial Self-Assembled Polymers: A Robust Route for Ultrahigh Efficient Encapsulation.

The control of cargo phase-transfer is of interest for many applications in science and technology. Herein, we report a simple, versatile and robust method to block the phase-transfer of cargo colloids by interfacial self-assembled amphiphilic polymer molecules. After simply increasing the concentration of amphiphilic polymers, the orientation of interfacial polymer molecules changed from flat to upright, forming a thick three-dimensional polymer layer at the oil-water interface. Even under fierce external force, this thick interfacial layer robustly prevented the phase-transfer of cargo colloids, resulting in an ultrahigh encapsulation efficiency (up to 97.1 %) for proteins and peptides. One single injection of high insulin-loaded microcomposites (58.3 wt%) kept the blood glucose level within the normoglycemic state for 10 days in type 1 diabetic rats. The mass of administrated amphiphilic polymers was 1889 times smaller than that of microcomposites prepared with non-amphiphilic ones.

Prediction of drug capturing by lipid emulsions in vivo for the treatment of a drug overdose.

Despite the successful treatment of drug intoxications, little information is available to quantitively predict the effect of lipid emulsions on pharmacokinetic features of overdosed drug molecules. We defined two new parameters, drug accommodation capacity and drug capture kinetics, to characterize the drug capture capability of lipid emulsions. By precisely characterizing their drug capture capability, the effect of lipid emulsions on pharmacokinetic features of overdosed drug molecules was quantitively described. This quantitative description enabled an accurate prediction of the reducing extent on the half-life and area under drug concentration-time curve, which was verified by the successful treatment of overdosed propafenone. Moreover, the capture effect prediction using drug capture capability was more accurate than that of directly using logP. Overall, the developed capture capability accurately described the effect of lipid emulsions on drug pharmacokinetic features, which can guide the clinical application of lipid emulsions for the treatment of drug overdose.

High drug-loaded microspheres enabled by controlled in-droplet precipitation promote functional recovery after spinal cord injury.

Drug delivery systems with high content of drug can minimize excipients administration, reduce side effects, improve therapeutic efficacy and/or promote patient compliance. However, engineering such systems is extremely challenging, as their loading capacity is inherently limited by the compatibility between drug molecules and carrier materials. To mitigate the drug-carrier compatibility limitation towards therapeutics encapsulation, we developed a sequential solidification strategy. In this strategy, the precisely controlled diffusion of solvents from droplets ensures the fast in-droplet precipitation of drug molecules prior to the solidification of polymer materials. After polymer solidification, a mass of drug nanoparticles is embedded in the polymer matrix, forming a nano-in-micro structured microsphere. All the obtained microspheres exhibit long-term storage stability, controlled release of drug molecules, and most importantly, high mass fraction of therapeutics (21.8-63.1 wt%). Benefiting from their high drug loading degree, the nano-in-micro structured acetalated dextran microspheres deliver a high dose of methylprednisolone (400 µg) within the limited administration volume (10 µL) by one single intrathecal injection. The amount of acetalated dextran used was 1/433 of that of low drug-loaded microspheres. Moreover, the controlled release of methylprednisolone from high drug-loaded microspheres contributes to improved therapeutic efficacy and reduced side effects than low drug-loaded microspheres and free drug in spinal cord injury therapy.

Surface Adsorption-Mediated Ultrahigh Efficient Peptide Encapsulation with a Precise Ratiometric Control for Type 1 and 2 Diabetic Therapy.

A surface adsorption strategy is developed to enable the engineering of microcomposites featured with ultrahigh loading capacity and precise ratiometric control of co-encapsulated peptides. In this strategy, peptide molecules (insulin, exenatide, and bivalirudin) are formulated into nanoparticles and their surface is decorated with carrier polymers. This polymer layer blocks the phase transfer of peptide nanoparticles from oil to water and, consequently, realizes ultrahigh peptide loading degree (up to 78.9%). After surface decoration, all three nanoparticles are expected to exhibit the properties of adsorbed polymer materials, which enables the co-encapsulation of insulin, exenatide, and bivalirudin with a precise ratiometric control. After solidification of this adsorbed polymer layer, the release of peptides is synchronously prolonged. With the help of encapsulation, insulin achieves 8 days of glycemic control in type 1 diabetic rats with one single injection. The co-delivery of insulin and exenatide (1:1) efficiently controls the glycemic level in type 2 diabetic rats for 8 days. Weekly administration of insulin and exenatide co-encapsulated microcomposite effectively reduces the weight gain and glycosylated hemoglobin level in type 2 diabetic rats. The surface adsorption strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performance of peptides, especially for the combination of peptides.

Neutrophil Cyto-Pharmaceuticals Suppressing Tumor Metastasis via Inhibiting Hypoxia-Inducible Factor-1α in Circulating Breast Cancer Cells.

Circulating tumor cells (CTCs) are reported as the precursor of tumor metastases, implying that stifling CTCs would be beneficial for metastasis prevention. However, challenges remain for the application of therapies that aim at CTCs due to lack of effective CTC-targeting strategy and sensitive therapeutic agents. Herein, a general CTC-intervention strategy based on neutrophil cyto-pharmaceuticals is proposed for suppressing CTC colonization and metastasis formation. Breast cancer 4T1 cells are infused as the mimic CTCs, and 4T1 cells trapped are first elucidated in neutrophil extracellular traps (NETs) expressing high levels of hypoxia-inducible factor-1α (HIF-1α) due to NET formation and thus promoting tumor cell colonization through enhanced migration, invasion and stemness. After verifying HIF-1α as a potential target for metastasis prevention, living neutrophil cyto-pharmaceuticals (CytPNEs) loaded with HIF-1α inhibitor are fabricated to therapeutically inhibit HIF-1α. It is demonstrated that CytPNEs can specially convey the HIF-1α inhibitor to 4T1 cells according to the inflammatory chemotaxis of neutrophils and down-regulate HIF-1α, thereby inhibiting metastasis and prolonging the median survival of mice bearing breast cancer lung metastasis. The research offers a new perspective for understanding the mechanism of CTC colonization, and puts forward the strategy of targeted intervention of CTCs as a meaningful treatment for tumor metastasis.

Inhibiting Phase Transfer of Protein Nanoparticles by Surface Camouflage-A Versatile and Efficient Protein Encapsulation Strategy.

Engineering a system with a high mass fraction of active ingredients, especially water-soluble proteins, is still an ongoing challenge. In this work, we developed a versatile surface camouflage strategy that can engineer systems with an ultrahigh mass fraction of proteins. By formulating protein molecules into nanoparticles, the demand of molecular modification was transformed into a surface camouflage of protein nanoparticles. Thanks to electrostatic attractions and van der Waals interactions, we camouflaged the surface of protein nanoparticles through the adsorption of carrier materials. The adsorption of carrier materials successfully inhibited the phase transfer of insulin, albumin, ß-lactoglobulin, and ovalbumin nanoparticles. As a result, the obtained microcomposites featured with a record of protein encapsulation efficiencies near 100% and a record of protein mass fraction of 77%. After the encapsulation in microcomposites, the insulin revealed a hypoglycemic effect for at least 14 d with one single injection, while that of insulin solution was only ∼4 h.

Polydopamine-Decorated Microcomposites Promote Functional Recovery of an Injured Spinal Cord by Inhibiting Neuroinflammation.

Neuroinflammation following spinal cord injury usually aggravates spinal cord damage. Many inflammatory cytokines are key players in neuroinflammation. Owing largely to the multiplicity of cytokine targets and the complexity of cytokine interactions, it is insufficient to suppress spinal cord damage progression by regulating only one or a few cytokines. Herein, we propose a two-pronged strategy to simultaneously capture the released cytokines and inhibit the synthesis of new ones in a broad-spectrum manner. To achieve this strategy, we designed a core/shell-structured microcomposite, which was composed of a methylprednisolone-incorporated polymer inner core and a biocompatible polydopamine outer shell. Thanks to the inherent adhesive nature of polydopamine, the obtained microcomposite (MP-PLGA@PDA) efficiently neutralized the excessive cytokines in a broad-spectrum manner within 1 day after spinal cord injury. Meanwhile, the controlled release of immunosuppressive methylprednisolone reduced the secretion of new inflammatory cytokines. Benefiting from its efficient and broad-spectrum capability in reducing the level of cytokines, this core/shell-structured microcomposite suppressed the recruitment of macrophages and protected the injured spinal cord, leading to an improved recovery of motor function. Overall, the designed microcomposite successfully achieved the two-pronged strategy in cytokine neutralization, providing an alternative approach to inhibit neuroinflammation in the injured spinal cord.

Microfluidic Nanoassembly of Bioengineered Chitosan-Modified FcRn-Targeted Porous Silicon Nanoparticles @ Hypromellose Acetate Succinate for Oral Delivery of Antidiabetic Peptides.

Microfluidics technology is emerging as a promising strategy in improving the oral delivery of proteins and peptides. Herein, a multistage drug delivery system is proposed as a step forward in the development of noninvasive therapies. Undecylenic acid-modified thermally hydrocarbonized porous silicon (UnPSi) nanoparticles (NPs) were functionalized with the Fc fragment of immunoglobulin G for targeting purposes. Glucagon-like peptide-1 (GLP-1) was loaded into the NPs as a model antidiabetic drug. Fc-UnPSi NPs were coated with mucoadhesive chitosan and ultimately entrapped into a polymeric matrix with pH-responsive properties by microfluidic nanoprecipitation. The final formulation showed a controlled and narrow size distribution. The pH-responsive matrix remained intact in acidic conditions, dissolving only in intestinal pH, resulting in a sustained release of the payload. The NPs presented high cytocompatibility and increased levels of interaction with intestinal cells when functionalized with the Fc fragment, which was supported by the validation of the Fc-fragment integrity after conjugation to the NPs. Finally, the Fc-conjugated NPs showed augmented GLP-1 permeability in an intestinal in vitro model. These results highlight the potential of microfluidics as an advanced technique for the preparation of multistage platforms for oral administration. Moreover, this study provides new insights on the potential of the Fc receptor transcytotic capacity for the development of targeted therapies.

Hierarchical structured and programmed vehicles deliver drugs locally to inflamed sites of intestine.

Orally administrable drug delivery vehicles are developed to manage incurable inflammatory bowel disease (IBD), however, their therapeutic outcomes are compromised by the side effects of systemic drug exposure. Herein, we use hyaluronic acid functionalized porous silicon nanoparticle to bridge enzyme-responsive hydrogel and pH-responsive polymer, generating a hierarchical structured (nano-in-nano-in-micro) vehicle with programmed properties to fully and sequentially overcome the multiple obstacles for efficiently delivering drugs locally to inflamed sites of intestine. After oral administration, the pH-responsive matrix protects the embedded hybrid nanoparticles containing drug loaded hydrogels against the spatially variable physiological environments of the gastrointestinal tract until they reach the inflamed sites of intestine, preventing premature drug release. The negatively charged hybrid nanoparticles selectively target the inflamed sites of intestine, and gradually release drug in response to the microenvironment of inflamed intestine. Overall, the developed hierarchical structured and programmed vehicles load, protect, transport and release drugs locally to inflamed sites of intestine, contributing to superior therapeutic outcomes. Such strategy could also inspire the development of numerous hierarchical structured vehicles by other porous nanoparticles and stimuli-responsive materials for the local delivery of various drugs to treat plenty of inflammatory gastrointestinal diseases, including IBD, gastrointestinal cancers and viral infections.

Impact of Pore Size and Surface Chemistry of Porous Silicon Particles and Structure of Phospholipids on Their Interactions.

By exploiting its porous structure and high loading capacity, porous silicon (PSi) is a promising biomaterial to fabricate protocells and biomimetic reactors. Here, we have evaluated the impact of physicochemical properties of PSi particles [thermally oxidized PSi, TOPSi; annealed TOPSi, AnnTOPSi; (3-aminopropyl) triethoxysilane functionalized thermally carbonized PSi, APTES-TCPSi; and thermally hydrocarbonized PSi, THCPSi] on their surface interactions with different phospholipids. All of the four phospholipids were similarly adsorbed by the surface of PSi particles, except for TOPSi. Among four PSi particles, TOPSi with hydrophilic surface and smaller pore size showed the weakest adsorption toward phosphatidylcholines. By increasing the pore size from roughly 12.5 to 18.0 nm (TOPSi vs AnnTOPSi), the quantity of phosphatidylcholines adsorbed by TOPSi was enhanced to the same level of hydrophilic APTES-TCPSi and hydrophobic THCPSi. The 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) exhibited the highest release ratio of phospholipids from all four PSi particles, and phosphatidylserine (DPPS) showed the lowest release ratio of phospholipids from PSi particles, except for TOPSi, which adsorbed less phospholipids due to the small pore size. There is consistency in the release extent of phospholipids from PSi particles and the isosteric heat of adsorption. Overall, our study demonstrates the importance of pore size and surface chemistry of PSi particles as well as the structure of phospholipids on their interactions. The obtained information can be employed to guide the selection of PSi particles and phospholipids to fabricate highly ordered structures, for example, protocells, or biomimetic reactors.

Engineered Multifunctional Albumin-Decorated Porous Silicon Nanoparticles for FcRn Translocation of Insulin.

The last decade has seen remarkable advances in the development of drug delivery systems as alternative to parenteral injection-based delivery of insulin. Neonatal Fc receptor (FcRn)-mediated transcytosis has been recently proposed as a strategy to increase the transport of drugs across the intestinal epithelium. FcRn-targeted nanoparticles (NPs) could hijack the FcRn transcytotic pathway and cross the epithelial cell layer. In this study, a novel nanoparticulate system for insulin delivery based on porous silicon NPs is proposed. After surface conjugation with albumin and loading with insulin, the NPs are encapsulated into a pH-responsive polymeric particle by nanoprecipitation. The developed NP formulation shows controlled size and homogeneous size distribution. Transmission electron microscopy (TEM) images show successful encapsulation of the NPs into pH-sensitive polymeric particles. No insulin release is detected at acidic conditions, but a controlled release profile is observed at intestinal pH. Toxicity studies show high compatibility of the NPs with intestinal cells. In vitro insulin permeation across the intestinal epithelium shows approximately fivefold increase when insulin is loaded into FcRn-targeted NPs. Overall, these FcRn-targeted NPs offer a toolbox in the development of targeted therapies for oral delivery of insulin.

Production of pure drug nanocrystals and nano co-crystals by confinement methods.

The use of drug nanocrystals in the drug formulation is increasing due to the large number of poorly water-soluble drug compounds synthetized and due to the advantages brought by the nanonization process. The downsizing processes are done using a top-down approach (milling and homogenization currently employed at the industrial level), while the crystallization process is performed by bottom-up techniques (e.g., antisolvent precipitation, use of supercritical fluids or spray and freeze drying). In addition, the production of nanocrystals in confined environment can be achieved within microfluidics channels. This review analyzes the processes for the preparation of nanocrystals and co-crystals, divided by top-down and bottom-up approaches, together with their combinations. The combination of both strategies merges the favorable features of each process and avoids the disadvantages of single processes. Overall, the applicability of drug nanocrystals is highlighted by the widespread research on the production processes at the engineering, pharmaceutical, and nanotechnology level.

Electrospun Polyhydroxybutyrate/Poly(ε-caprolactone)/Sol-Gel-Derived Silica Hybrid Scaffolds with Drug Releasing Function for Bone Tissue Engineering Applications.

Electrospun hybrid scaffolds are an effective platform to deliver drugs site specifically for the prevention and treatment of diseases in addition to promote tissue regeneration because of the flexibility to load drugs therein. In the present study, electrospun hybrid scaffolds containing antibiotics were developed to support cellular activities and eliminate potential postoperative inflammation and infection. As a model drug, levofloxacin (LFX) was successfully incorporated into pure polyhydroxybutyrate/poly(ε-caprolactone) (PHB/PCL) scaffolds and PHB/PCL/sol-gel-derived silica (SGS) scaffolds. The influence of LFX on the morphology, mechanical performance, chemical structure, drug release profile, and antibacterial effect of the scaffolds was thoroughly and comparatively investigated. MG-63 osteoblast-like cell cultivation on both scaffolds certified that LFX inclusion did not impair the biocompatibility. In addition to the favorable cellular proliferation and differentiation, scaffolds containing both LFX and SGS displayed highly increased mineralization content. Therefore, the present multifunctional hybrid scaffolds are promising in tissue engineering applications.

Tailoring Porous Silicon for Biomedical Applications: From Drug Delivery to Cancer Immunotherapy.

In the past two decades, porous silicon (PSi) has attracted increasing attention for its potential biomedical applications. With its controllable geometry, tunable nanoporous structure, large pore volume/high specific surface area, and versatile surface chemistry, PSi shows significant advantages over conventional drug carriers. Here, an overview of recent progress in the use of PSi in drug delivery and cancer immunotherapy is presented. First, an overview of the fabrication of PSi with various geometric structures is provided, with particular focus on how the unique geometry of PSi facilitates its biomedical applications, especially for drug delivery. Second, surface chemistry and modification of PSi are discussed in relation to the strengthening of its performance in drug delivery and bioimaging. Emerging technologies for engineering PSi-based composites are then summarized. Emerging PSi advances in the context of cancer immunotherapy are also highlighted. Overall, very promising research results encourage further exploration of PSi for biomedical applications, particularly in drug delivery and cancer immunotherapy, and future translation of PSi into clinical applications.

Biodegradable Spheres Protect Traumatically Injured Spinal Cord by Alleviating the Glutamate-Induced Excitotoxicity.

New treatment strategies for spinal cord injury with good therapeutic efficacy are actively pursued. Here, acetalated dextran (AcDX), a biodegradable polymer obtained by modifying vicinal diols of dextran, is demonstrated to protect the traumatically injured spinal cord. To facilitate its administration, AcDX is formulated into microspheres (≈7.2 µm in diameter) by the droplet microfluidic technique. Intrathecally injected AcDX microspheres effectively reduce the traumatic lesion volume and inflammatory response in the injured spinal cord, protect the spinal cord neurons from apoptosis, and ultimately, recover the locomotor function of injured rats. The neuroprotective feature of AcDX microspheres is achieved by sequestering glutamate and calcium ions in cerebrospinal fluid. The scavenging of glutamate and calcium ion reduces the influx of calcium ions into neurons and inhibits the formation of reactive oxygen species. Consequently, AcDX microspheres attenuate the expression of proapoptotic proteins, Calpain, and Bax, and enhance the expression of antiapoptotic protein Bcl-2. Overall, AcDX microspheres protect traumatically injured spinal cord by alleviating the glutamate-induced excitotoxicity. This study opens an exciting perspective toward the application of neuroprotective AcDX for the treatment of severe neurological diseases.