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Traditional pesticide emulsion formulation may exert deleterious effects on the environment and even induce stress on nontarget crops in the vicinity. In this study, γ-cyclodextrin (γ-CD)-encapsulated azobenzene derivative nanovesicles were synthesized and loaded with pendimethalin to obtain pendimethalin-loaded γ-CD/azobenzene derivative nanovesicles. Upon exposure to ultraviolet irradiation or sunlight, the azobenzene derivatives are converted from the trans- to cis- configuration, leading to the dissociation of the ternary host–guest complexes, resulting in the vesicle rupture and the subsequent release of pendimethalin. Further investigations were conducted on the γ-CD/azobenzene nanovesicles. According to the release characteristics of herbicides, the release rate of pendimethalin under ultraviolet light (365 nm) or sunlight conditions reached 88.3 ± 3%, which was 4.3 times higher than that under dark conditions, demonstrating excellent photocontrolled release behavior. Pot experiments showed that the herbicidal activity of pendimethalin-loaded nanovesicles against Portulaca oleracea (L.) and Echinochloa crusgalli (L.) Beauv. at the recommended dose was comparable to that of the pendimethalin technical under illuminated conditions. Furthermore, genotoxicity experiments reveal a notable increase in the mitotic index of onion root tip cells treated with pendimethalin-loaded nanovesicles, indicating that it had minimal inhibitory effect on cell metabolism and the genotoxicity was lower than that of pendimethalin technical. Pendimethalin-loaded nanovesicles exhibited favorable stability and photoresponsive performance. These findings reveal a promising avenue for responsive material design and release modulation using such nanovesicle systems, providing insights into their potential applications in targeted pesticide delivery systems. [ABSTRACT FROM AUTHOR]

How to maximize the targeted accumulation of nanomedicine is still the goal of scientists. Using artificial intelligence technology to develop nanosystems with active targeting capabilities to promote effective drug delivery is an excellent tumor targeting therapy strategy. It is reported that ferroptosis therapy has a significant therapeutic effect on migratory breast cancer. In this study, we constructed a comprehensive ferroptosis treatment strategy for multiple target intervention of migratory breast cancer by combining magnetically driven and exosome-mediated tumor double-targeting complex nanovesicles (A15-THP-1exo-(SPION/Sor)) with active targeting and passive targeting transport modes. The complex nanovesicles contain a functional exosome with high expression of A15 protein, which is used to mediate the nanovesicles to achieve the active tumor targeting effect; superparamagnetic nanoparticles can not only mediate the passive targeting of tumor by nanovesicles but also act as an inducer of ferroptosis. To implement multi-target intervention to maximize the therapeutic effect of ferroptosis by complex nanovesicles, the ferroptosis inducer sorafenib and iron supplement magnetic nanoparticles were combined. Ferroptosis is enhanced by blocking the xCT/GSH/GPX-4 system and increasing iron supply. The results in vivo and in vitro showed that the complex nanovesicles had significant tumor targeting and had an excellent ferroptosis treatment effect on migratory breast cancer. [ABSTRACT FROM AUTHOR]

Chemotherapeutics commonly exhibit low bioavailability and systemic adverse effects. Supramolecular nanovesicles, such as pillar-[n]-arenes, calix-[n]-arenes, cucurbit-[n]-urils (CBs), and cyclodextrins, have been introduced as promising nanocarriers due to their remarkable encapsulation capacity and ability to host hydro-philic/-phobic guest molecules. Additionally, such nanovesicles can be decorated with various stimuli-responsive entities to enable drug targeting and controlled drug release. Self-assembly of amphiphilic cavitands and host–guest complexation represent the two common approaches for preparation of supramolecular nanovesicles with customizable surfaces capable of accommodating different biologically active guest molecules. CBs have been used as smart and multifunctional host macromolecules in cancer therapy. CBs are fabricated via a condensation reaction between formaldehyde and glycoluril units generating barrel-shaped supramolecules with partially enclosed cavities. The unique structure of CBs surrounding an internal hydrophobic cavity allows them to accommodate cationic and neutral guest molecules via ion-dipole and hydrophobic interactions, respectively. Additionally, CBs are stable, safe, and biocompatible, and their surfaces can be decorated with various functional targeting moieties. These advantages have promoted CBs as promising candidates for stimuli-responsive targeted delivery of chemotherapeutics. This review presents the most recent advances in the design of stimuli-responsive nanosystems based on CBs for effective cancer treatment. [ABSTRACT FROM AUTHOR]

Skin trauma often results from pain, swelling, and scarring and can significantly interfere with daily activities. Extracts from the American cockroach, a rapidly reproducing insect, have been recognized for therapeutic properties in wound management. Traditional extraction methods use solvents such as ethanol to obtain the active compounds, but these methods may compromise the intrinsic biological properties of American cockroach extracts. In this study, we investigated the use of nanovesicles isolated from fresh American cockroaches in skin wound treatment and focused on their biological characteristics and therapeutic efficacy. Fresh and dried American cockroach nanovesicles (F-ACNVs and D-ACNVs, respectively) were procured via ultrahigh-speed centrifugation. We found that F-ACNVs exhibited superior cell proliferation-promoting activity. By employing metabolomics, proteomics, and long noncoding RNA (lncRNA) omics, we identified a rich repertoire of metabolites, proteins, and lncRNAs within F-ACNVs. In vitro and in vivo experiments demonstrated that F-ACNVs significantly enhanced the proliferation and migration of human umbilical vein endothelial cells (HUVECs) and human skin keratinocytes (HACATs) as well as the repair of skin mechanical trauma. These effects may be mediated through the activation of angiogenic signaling pathways. Our research introduces a novel therapeutic strategy for treating skin trauma and offers insight into the medicinal potential of insects such as the American cockroach while emphasizing the importance of preserving the intrinsic biological properties of insects for optimal therapeutic outcomes.

Photoresponsive liposomes are controlled-release liposomes modified by photoresponsive materials. They use light with high spatial and temporal precision as a means of regulation. After excitation by light at appropriate wavelengths, photoresponsive liposomes can influence the permeability of phospholipid bilayers through the photothermal or photoisomerization effect of photoresponsive materials. The photothermal effect causes the phospholipid layer to become dispersed by local heating, and the photoisomerization effect modulates the release behavior by establishing permeation channels on the phospholipid layer through changes in the dipole moments of azobenzene derivatives. Currently, photoresponsive liposomes are widely used as a cutting-edge strategy for nanomedicine. In this paper, three types of photoresponsive liposomes based on organic photosensitizers, Au nanoparticles, and azobenzene derivatives with abundant research reports were introduced based on the differences in the photoresponse principles and forms of different photoresponsive materials. This review aims to reflect the differences in the structures, properties, photoresponsive materials, and principles of action of different photoresponsive liposomes. Moreover, this work outlines the current status of their application in the field of nanomedicine. [ABSTRACT FROM AUTHOR]

Hybrid lipid/polymer membranes offer superior tunability over lipid-only systems, for a wide range of potential applications in surface modification and drug delivery, including nanovesicles (NVs) for mRNA-based therapeutics. The polymeric component can be readily modified for specific properties, and the lipid-to-polymer composition can be adjusted for even finer control. However, these materials are still an emerging field of study, and their potential is not yet fully understood. Modulating and modeling the ζ potential of these membranes is a critical step toward controlling their surface interactions. In this study, we performed ζ potential analysis on NVs with diameters of ∼100 nm made from lipids (1,2-dioleoyl-3-trimethylammonium propane, 1,2-dioleoyl-sn-glycero-3-phospho-l-serine, and 1,2-dioleoyl-sn-glycero-3-phosphocholine) and amphiphilic block copolymers (PEO–PBd, PBd–PEO–NH3+, and PBd–PEO–COO–) at various compositions. This study revealed that NVs composed of the polymer PEO–PBd are surprisingly resilient to attempts to change their ζ potential with the addition of anionic or cationic lipids, which could limit their utility for drug-delivery applications and strategies to modify their surface chemistry. To overcome these limitations and explain these results, we devised a simple predictive and explanatory model that allows estimation of the ζ potential of hybrid NVs containing charged lipids. Our results indicate that the location of the charged groups can be controlled in order to impact the visibility of those charged groups to the surrounding materials and tissues that synthetic NVs interact with. We anticipate that our approach will greatly facilitate the design and modulation of the ζ potential and other properties of polymer NVs and other biomimetic membrane materials for nanomedicine and nanobiosensors. [ABSTRACT FROM AUTHOR]

The efficacy of the treatment of bacterial infection is seriously reduced because of antibiotic resistance; thus, therapeutic solutions against drug-resistant microbes are necessary. Nanoparticle-based solutions are particularly promising for meeting this challenge because they can offer intrinsic antimicrobial activity and sustained drug release at the target site. Herein, we present a newly developed nanovesicle system of the quatsome family, composed of l-prolinol-derived surfactants and cholesterol, which has noticeable antibacterial activity even on Gram-negative strains, demonstrating great potential for the treatment of bacterial infections. We optimized the vesicle stability and antibacterial activity by tuning the surfactant chain length and headgroup charge (cationic or zwitterionic) and show that these quatsomes can furthermore serve as nanocarriers of pharmaceutical actives, demonstrated here by the encapsulation of (+)-usnic acid, a natural substance with many pharmacological properties. [ABSTRACT FROM AUTHOR]

Spray-induced gene silencing (SIGS) presents a promising RNA interference (RNAi)-based crop protection strategy against eukaryotic phytopathogens. However, the application of SIGS faces challenges, such as the limited uptake of dsRNA by certain pathogens and the instability of dsRNA in the environment. This study introduces innovative biomimetic nanovesicles, called extracellular vesicle (EV) mimetic chimeric nanovesicles (ECNs), assembled from tomato leaf cell membranes and cationic sterosomes via the freeze-thaw method. Similar to the function of EVs in nucleic acid transport between cells, ECNs serve as a hybrid nanosystem to overcome the challenge of delivering exogenous dsRNA in Phytophthora infestans . When applied to SIGS, the superiority of ECNs in crop protection becomes more apparent, including high loading and protection of dsRNA, improved biosafety, and efficient internalization into pathogen and plant cells, all of which significantly enhance the efficacy of RNAi in preventing early infection of P. infestans to susceptible tomato plants. This study demonstrates that ECNs are promising RNA delivery vehicles and will promote the use of SIGS-based RNA pesticides in sustainable agricultural production.

The compound 2,4,6-trichlorophenol poses significant risks to both the aquatic environment and human health. Its inherent persistence and stability present challenges in achieving complete purification, thus warranting its inclusion as a priority pollutant. The present study reports the development of an amphiphilic small-molecule compound that self-assembles into nanovesicles exhibiting remarkable adsorption and photodegradation capabilities. Through the synergistic effects of hydrogen bonding, van der Waals forces, π-π interactions, and electrostatic interactions, these vesicles efficiently adsorb 2,4,6-trichlorophenol from aqueous solutions within 1 min while demonstrating exceptional environmental stability and broad applicability. Upon self-assembly into vesicles, not only are more adsorption sites exposed, but charge separation and migration within the vesicles are also facilitated. Through the synergistic effects of adsorption and photodegradation, complete removal of 2,4,6-trichlorophenol in aqueous solution can be achieved within 8 h while exhibiting excellent recycling capability. This approach offers a viable strategy for designing and synthesizing pure organic photodegradable materials.

The combination of anti-rheumatoid arthritis (RA) drugs methotrexate (MTX) and baricitinib (BTN) has been reported to improve RA treatment efficacy. However, study on the strategy of combination is elusive when considering the benefit of the synergy between MTX and BTN. In this study, we found that the N-heterocyclic rings in the MTX and BTN offer hydrogen bonds and π-π stacking interactions, driving the formation of exquisite vesicular morphology of nanovesicles, denoted as MB NVs. The MB NVs with the MTX/BTN weight ratio of 2:1, MB NVs (2:1), showed an improved anti-RA effect through the synergy between the anti-inflammatory and antiproliferative responses. This work presents that the intermolecular interactions between drug molecules could mediate the coassembly behavior into nanomedicine as well as the therapy synergy both in vitro and in vivo , which may provide further understanding on the rational design of combination nanomedicine for therapeutic purposes.

The rapid proliferative biological behavior of primary foci of anaplastic thyroid cancer (ATC) makes it a lethal tumor. According to the specific iodine uptake capacity of thyroid cells and enhanced endocytosis of ATC cells, we designed a kind of nanoclay drug-loading system and showed a promising treatment strategy for ATC. Introducing potassium iodide (KI) improves the homoaggregation of clay nanoparticles and then affects the distribution of nanoparticles in vivo, which makes KI@DOX-Kaolin MeOH enriched almost exclusively in thyroid tissue. Simultaneously, the improvement of dispersibility of KI@DOX-Kaolin MeOH changes the target uptake of ATC cells by improving the endocytosis and nanoparticle-induced autophagy, which regulate the production of autolysosomes and autophagy-enhanced chemotherapy, eventually contributing to a tumor inhibition rate of more than 90% in the primary foci of ATC. Therefore, this facile strategy to improve the homoaggregation of nanoclay by introducing KI has the potential to become an advanced drug delivery vehicle in ATC treatment.

Osteoporosis is a global disease caused by abnormal overactivation of osteoclasts. The acidic environment in sealing zone of osteoclasts with H + pumped from cytoplasm is critical to the maturation of osteoclasts. Therefore, reducing the intracellular H + concentration can reduce the H + secretion of osteoclasts from the source. In our study, we developed a novel nanovesicle which encapsulates Na 2 HPO 4 with a liposome hybridizes with preosteoclast membrane (Na 2 HPO 4 @Lipo-pOCm). These nanovesicles release Na 2 HPO 4 into the preosteoclast by targeting preosteoclasts and membrane fusion, reducing the intracellular H + concentration, and achieve biological cascade regulation of osteoclasts through simple pH regulation. In vitro and in vivo experiments confirmed that these nanovesicles reduce mitochondrial membrane potential by decreasing intracellular H + concentration, thereby reducing the ROS in osteoclasts as well as the expression of the upstream transcription factor FOXM1 of Acp5. In short, this nanovesicle can significantly inhibit the osteoclasts and ameliorate osteoporosis caused by OVX.

Photothermal therapy (PTT) has emerged as a promising alternative or supplement to cancer treatments. While PTT induces the ablation of solid tumors, its efficiency is hampered by self-recovery within impaired cancer cells through glycolysis and respiration metabolism. Based on this, the introduction of hydrogen sulfide (H 2 S)-mediated respiration inhibition is a good choice to make up for the PTT limitation. Herein, nanovesicles ( NP1 ) are integrated by a hypoxia-responsive conjugated polymer ( P1 ), polymetric H 2 S donor ( P2 ), and near-infrared (NIR) light-harvesting aza-BODIPY dye ( B1 ) for the delivery of H 2 S and synergistic H 2 S gas therapy/PTT. The scaffold of NP1 undergoes disassembly in the hypoxic environments, thus triggering the hydrolysis of P2 to continuously long-term release H 2 S. Dependent on the superior photothermal ability of B1 , NP1 elicits high photothermal conversion efficiency (η = 19.9%) under NIR light irradiation for PTT. Moreover, NP1 serves as in situ H 2 S bombers in the hypoxic tumor environment and suppresses the mitochondrial respiration through inhibiting expression of cytochrome c oxidase (COX IV) and cutting off the adenosine triphosphate (ATP) generation. Both in vitro and in vivo results demonstrate good antitumor efficacy of H 2 S gas therapy/PTT, which will be recommended as an advanced strategy for cancer therapeutics.

Liver cancer cells evade immune surveillance and anticancer response through various pathways, including the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) immune checkpoint axis that exhausts CD8 + T cells. Inhibitors or antibodies of the PD-L1/PD-1 signaling axis are considered promising drugs for cancer immunotherapy and exhibit favorable clinical responses. However, adverse effects, immune tolerance, and delivery barriers of most patients limit the clinical application of PD-L1/PD-1 antibodies. Thus, it is critical to develop a novel delivery strategy to enhance anticancer immunotherapy. In this study, we bioengineered cell membrane-derived nanovesicles (NVs) presenting PD-1 proteins and dibenzocyclooctyne (DBCO) to encapsulate 1-methyltryptophan (1-MT) (DBCO+PD-1@1-MT NVs). DBCO can specifically interact with N -azidoacetylmannosamine-tetraacetylate (Ac 4 ManN 3 ) labeled onto metabolic cells for targeted killing of cancers. We next explored the effects of DBCO+PD-1@1-MT NVs on anticancer Hepa1-6 cells in vitro and in vivo. Results showed that PD-1@1-MT NVs dramatically inhibited Hepa1-6 proliferation, promoted peripheral blood mononuclear cell (PBMC) expansion, and strengthened anticancer therapy via blockading the PD-1/PD-L1 immune checkpoint axis, owing to the 1-methyltryptophan (1-MT) enhancement of anticancer immunotherapy efficacy through suppressing the activity of indoleamine 2,3-dioxygenase (IDO). Thus, 1-MT was encapsulated into PD-1 NVs to synergistically enhance cancer immunotherapy. Results have shown that PD-1@1-MT NVs obviously attenuated tumor growth, promoting IFN-γ production, increasing the T cells infiltration in tumors and spleens, and improving the survival period of tumor-bearing mice compared to monotherapy. Therefore, we propose a promising delivery strategy of the combination of DBCO+PD-1 NVs and 1-MT for specific and effective cancer-targeted immunotherapy.

The synthesis and study of the tripeptide Arg-Gly-Asp (RGD), the binding site of different extracellular matrix proteins, e.g., fibronectin and vitronectin, has allowed the production of a wide range of cell adhesive surfaces. Although the surface density and spacing of the RGD peptide at the nanoscale have already shown a significant influence on cell adhesion, the impact of its hierarchical nanostructure is still rather unexplored. Accordingly, a versatile colloidal system named quatsomes, based on fluid nanovesicles formed by the self-assembling of cholesterol and surfactant molecules, has been devised as a novel template to achieve hierarchical nanostructures of the RGD peptide. To this end, RGD was anchored on the vesicle's fluid membrane of quatsomes, and the RGD-functionalized nanovesicles were covalently anchored to planar gold surfaces, forming a state of quasi-suspension, through a long poly(ethylene glycol) (PEG) chain with a thiol termination. An underlying self-assembled monolayer (SAM) of a shorter PEG was introduced for vesicle stabilization and to avoid unspecific cell adhesion. In comparison with substrates featuring a homogeneous distribution of RGD peptides, the resulting hierarchical nanoarchitectonic dramatically enhanced cell adhesion, despite lower overall RGD molecules on the surface. The new versatile platform was thoroughly characterized using a multitechnique approach, proving its enhanced performance. These findings open new methods for the hierarchical immobilization of biomolecules on surfaces using quatsomes as a robust and novel tissue engineering strategy.

Poly(ionic liquid)s (PIL) are common precursors for heteroatom-doped carbon materials. Despite a relatively higher carbonization yield, the PIL-to-carbon conversion process faces challenges in preserving morphological and structural motifs on the nanoscale. Assisted by a thin polydopamine coating route and ion exchange, imidazolium-based PIL nanovesicles were successfully applied in morphology-maintaining carbonization to prepare carbon composite nanocapsules. Extending this strategy further to their composites, we demonstrate the synthesis of carbon composite nanocapsules functionalized with iron nitride nanoparticles of an ultrafine, uniform size of 3-5 nm (termed "Fe x N@C"). Due to its unique nanostructure, the sulfur-loaded Fe x N@C electrode was tested to efficiently mitigate the notorious shuttle effect of lithium polysulfides (LiPSs) in Li-S batteries. The cavity of the carbon nanocapsules was spotted to better the loading content of sulfur. The well-dispersed iron nitride nanoparticles effectively catalyze the conversion of LiPSs to Li 2 S, owing to their high electronic conductivity and strong binding power to LiPSs. Benefiting from this well-crafted composite nanostructure, the constructed Fe x N@C/S cathode demonstrated a fairly high discharge capacity of 1085 mAh g -1 at 0.5 C initially, and a remaining value of 930 mAh g -1 after 200 cycles. In addition, it exhibits an excellent rate capability with a high initial discharge capacity of 889.8 mAh g -1 at 2 C. This facile PIL-to-nanocarbon synthetic approach is applicable for the exquisite design of complex hybrid carbon nanostructures with potential use in electrochemical energy storage and conversion.

Mesenchymal stem cells (MSCs) repair injured tissues mainly through their paracrine actions. One of the important paracrine components of MSC secretomes is the extracellular vesicle (EV). The therapeutic potential of MSC-EVs has been established in various cardiac injury preclinical models. However, the large-scale production of EVs remains a challenge. We sought to develop a scale-up friendly method to generate a large number of therapeutic nanovesicles from MSCs by extrusion. Those extruded nanovesicles (NVs) are miniature versions of MSCs in terms of surface marker expression. The yield of NVs is 20-fold more than that of EVs. In vitro , cell-based assays demonstrated the myocardial protective effects and therapeutic potential of NVs. Intramyocardial delivery of NVs in the injured heart after ischemia-reperfusion led to a reduction in scar sizes and preservation of cardiac functions. Such therapeutic benefits are similar to those injected with natural EVs from the same MSC parental cells. In addition, NV therapy promoted angiogenesis and proliferation of cardiomyocytes in the post-injury heart. In summary, extrusion is a highly efficient method to generate a large quantity of therapeutic NVs that can potentially replace extracellular vesicles in regenerative medicine applications.

The photostability and dispersity under aggregation states always become an obstacle for the development of small-molecular organic dye (SMOD) composites. Herein, a novel supramolecular assembly strategy with a two-step assembly method is implemented to encapsulate SMODs for improving their photostability and acquiring uniformly dispersed nanoaggregates in aqueous solution. By the novel assembly strategy, photodegradation rates of the anthraquinone-type dyes can decrease significantly, and the stability of dispersed nanoassembly bodies can be improved in solution. Based on the two-step supramolecular assembly strategy, a new kind of aqueous processing composite system can be developed for preparing multiband laser-responsive devices and in situ healing of optical composite films. This two-step supramolecular assembly strategy can provide a new template and reference for improving the defects of SMODs and fabricating high-performance optical devices.

Fabry disease is a rare lysosomal storage disorder characterized by a deficiency of α-galactosidase A (GLA), a lysosomal hydrolase. The enzyme replacement therapy administering naked GLA shows several drawbacks including poor biodistribution, limited efficacy, and relatively high immunogenicity in Fabry patients. An attractive strategy to overcome these problems is the use of nanocarriers for encapsulating the enzyme. Nanoliposomes functionalized with RGD peptide have already emerged as a good platform to protect and deliver GLA to endothelial cells. However, low colloidal stability and limited enzyme entrapment efficiency could hinder the further pharmaceutical development and the clinical translation of these nanoformulations. Herein, the incorporation of the cationic miristalkonium chloride (MKC) surfactant to RGD nanovesicles is explored, comparing two different nanosystems-quatsomes and hybrid liposomes. In both systems, the positive surface charge introduced by MKC promotes electrostatic interactions between the enzyme and the nanovesicles, improving the loading capacity and colloidal stability. The presence of high MKC content in quatsomes practically abolishes GLA enzymatic activity, while low concentrations of the surfactant in hybrid liposomes stabilize the enzyme without compromising its activity. Moreover, hybrid liposomes show improved efficacy in cell cultures and a good in vitro/in vivo safety profile, ensuring their future preclinical and clinical development.

Sonodynamic therapy (SDT), as a new method of non-invasive tumor treatment developed from photodynamic therapy (PDT), can overcome the disadvantage of poor laser penetration while retaining the function of PDT. However, the lack of efficient sonosensitizer accumulation and the hypoxic environment in tumor sites limited the therapeutic efficacy of SDT. Here, we constructed a highly efficient liquid fluorocarbon-encapsulated polymeric nanovesicle for enhanced sonodynamic efficacy as well as tumor hypoxia relief. This multifunctional nanovesicle was constructed by fluorinated cationic polymer C 9 F 17 -PAsp(DET) with PEG-conjugated protoporphyrin IX (PEG-PpIX) modification, which could yield the simultaneous loading of perfluorohexane (PFH) and oxygen. We found that the PAsp(DET)-PpIX-PEG@PFH nanovesicles could not only generate the reactive oxygen species (ROS) under ultrasound irradiation after intravenous ( i . v .) injection but also could generate and prolong the ROS under nanovesicle preparation by ultrasonication in vitro , so-called the ″exogenous ROS", which might result in enhanced cytotoxicity in tumor tissue. Furthermore, oxygen-loaded PAsp(DET)-PpIX-PEG nanovesicles could not only reduce therapeutic resistance by relieving tumor hypoxia but also increase ROS production for enhanced sonodynamic therapy. An in vivo study revealed that the nanovesicles could accumulate in the tumor site after i.v. injection and achieved remarkable tumor growth inhibition in both with and without preloaded oxygen groups, which indicated that the nanovesicle system could efficiently achieve oxygen loading during in vivo circulation and provide a better solution for SDT application.

Polymeric nanovehicles have been widely applied in many fields, but during the process of preparation, it is still hard to reach the balance between precise structure control and mass production. In the present work, using industrial pixel grids as the macroscopic template, we applied dual effects of confinement and dielectric difference to speed up the self-assembly of polymeric nanovehicles, even to regulate the generated mesostructures and cargo loading. Within 2 min, a poly(ethylene glycol)- block -poly(d,l-lactide acid) (PEG- b -PDLLA) amphiphilic block copolymer layer was rapidly pushed off and broken down into uniform nanoparticles at 40 V. Hereinto, increasing volume of the outer aqueous phase in pixel grids favored the architectonic transformation of the generated nanovehicles from solid micelles with a diameter of 95 nm to hollow vesicles with a diameter of 232 nm. In particular, all the elements from the confinement cells to the preparation process can be completed via wet printing. Electric-field-induced pixel template technology is facile, cheap, controllable, and recyclable, and it is anticipated to promote continuous and bulk production of polymeric nanovehicles.

We report development and characterization of cell-engineered nanovesicles made from mesenchymal stem cells (MSCNVs), which have more than 300 times higher productivity than natural extracellular vesicles (EVs). MSCNVs had similar morphological characteristics to MSCEVs but have molecular characteristics that more resemble MSCs than MSCEVs. In vitro MSCNV treatment increased the proliferation and migration of primary skin fibroblasts and showed better effects than treatment using natural MSCEVs. Quantitative real-time PCR analysis showed increased expression of growth factors in MSCNV-treated skin fibroblasts. Intraperitoneal injection of MSCNVs into syngeneic mice induced mild local inflammation, which resulted in recruitment of immune cells to the injection site. In vivo MSCNV treatment of a mouse skin wound accelerated its healing; this acceleration by MSCNVs may occur by promoting blood vessel formation at the wound site. These results indicate the promise of MSCNVs as agents for regenerative medicine.

Ischemic stroke is an acute and severe neurological disease, resulting in disability and death. Reperfusion to an ischemic brain is a means to reverse brain damage after stroke; however, this causes secondary tissue damage induced by inflammation responses, called ischemia/reperfusion (I/R) injury. Adhesion of neutrophils to endothelial cells underlies the initiation of inflammation in I/R. Inspired by this interaction, we report a drug delivery system comprised of neutrophil membrane-derived nanovesicles loaded with Resolvin D2 (RvD2) that can enhance resolution of inflammation, thus protecting brain damage during ischemic stroke. In the study, the middle cerebral artery occlusion (MCAO) mouse model was developed to mimic ischemic stroke. Using intravital microscopy of a live mouse brain, we visualized the binding of nanovesicles to inflamed brain vasculature for delivery of therapeutics to ischemic stroke lesions in real-time. We also observed that RvD2-loaded nanovesicles dramatically decreased inflammation in ischemic stroke and improved mouse neurological functions. Our study provides a strategy to inhibit neuroinflammation using neutrophil-derived nanovesicles for ischemic stroke therapy.

Specific drug delivery to metastatic tumors remains a great challenge for antimetastasis therapy. We herein report a bioengineered macrophage-based delivery system (LD-MDS) that can be preferentially delivered to lung metastases and intelligently transformed into nanovesicles and secondary nanovesicles for antimetastasis therapy. LD-MDS was prepared by anchoring a legumain-specific propeptide of melittin (legM) and cytotoxic soravtansine (DM4) prodrug onto the membrane of living macrophages. LD-MDS is responsively activated by legumain protease and converted into DM4-loaded exosome-like nanovesicles (DENs), facilitating efficient internalization by metastatic 4T1 cancer cells and considerable cell death. Afterward, the damaged 4T1 cells can release secondary nanovesicles and free drug molecules to destroy neighboring cancer cells. In vivo, LD-MDS displays superior targeting efficiency for lung metastatic lesions with diameters less than 100 μm and remarkably inhibits lung metastasis. This study provides a new opportunity to explore endogenous macrophages as living drug delivery vehicles with controlled drug release to target metastatic lung tumors.

Human mesenchymal stem cell (hMSC)-derived exosomes have been spotlighted as a promising therapeutic agent for cell-free regenerative medicine. However, poor organ-targeting ability and insufficient therapeutic efficacy of systemically injected hMSC-exosomes were identified as critical limitations for their further applications. Therefore, in this study we fabricated iron oxide nanoparticle (IONP)-incorporated exosome-mimetic nanovesicles (NV-IONP) from IONP-treated hMSCs and evaluated their therapeutic efficacy in a clinically relevant model for spinal cord injury. Compared to exosome-mimetic nanovesicles (NV) prepared from untreated hMSCs, NV-IONP not only contained IONPs which act as a magnet-guided navigation tool but also carried greater amounts of therapeutic growth factors that can be delivered to the target cells. The increased amounts of therapeutic growth factors inside NV-IONP were attributed to IONPs that are slowly ionized to iron ions which activate the JNK and c-Jun signaling cascades in hMSCs. In vivo systemic injection of NV-IONP with magnetic guidance significantly increased the amount of NV-IONP accumulating in the injured spinal cord. Accumulated NV-IONP enhanced blood vessel formation, attenuated inflammation and apoptosis in the injured spinal cord, and consequently improved spinal cord function. Taken together, these findings highlight the development of therapeutic efficacy-potentiated extracellular nanovesicles and demonstrate their feasibility for repairing injured spinal cord.

Although cocooning explant-derived cardiac stem cells (EDCs) in protective nanoporous gels (NPGs) prior to intramyocardial injection boosts long-term cell retention, the number of EDCs that finally engraft is trivial and unlikely to account for salutary effects on myocardial function and scar size. As such, we investigated the effect of varying the NPG content within capsules to alter the physical properties of cocoons without influencing cocoon dimensions. Increasing NPG concentration enhanced cell migration and viability while improving cell-mediated repair of injured myocardium. Given that the latter occurred with NPG content having no detectable effect on the long-term engraftment of transplanted cells, we found that changing the physical properties of cocoons prompted explant-derived cardiac stem cells to produce greater amounts of cytokines, nanovesicles, and microRNAs that boosted the generation of new blood vessels and new cardiomyocytes. Thus, by altering the physical properties of cocoons by varying NPG content, the paracrine signature of encapsulated cells can be enhanced to promote greater endogenous repair of injured myocardium.

The combination of multiple modalities has shown great potential in cancer treatment with improved therapeutic effects and minimized side effects. Here, we fabricated a type of doxorubicin-encapsulated biomimetic nanovesicle (NV) by a facile method with near-infrared dye insertion in the membrane for combinatorial photothermal and chemotherapy. With innate biomimetic properties, NVs enhanced the uptake by tumor cells while reducing the phagocytosis of macrophages. Upon laser irradiation, NVs can convert the absorbed fluorescent energy into heat for effective tumor killing. Hyperthermia can further induce membrane ablation of NVs to accelerate the release of chemotherapeutic drug for potent cytotoxicity to tumor cells. The NVs improved drug accumulation and showed a more efficient in vivo photothermal effect with a rapid temperature increase in tumors. Moreover, the NV-based combinational photothermal and chemotherapy exhibited significant tumor growth suppression with a high inhibitory rate of 91.6% and negligible systemic toxicity. The results indicate that NVs could be an appealing vehicle for combinational cancer treatment.

Nanovesicles (∼100 nm) are ubiquitous in cell biology and an important vector for drug delivery. Mechanical properties of vesicles are known to influence cellular uptake, but the mechanism by which deformation dynamics affect internalization is poorly understood. This is partly due to the fact that experimental studies of the mechanics of such vesicles remain challenging, particularly at the nanometer scale where appropriate theoretical models have also been lacking. Here, we probe the mechanical properties of nanoscale liposomes using atomic force microscopy (AFM) indentation. The mechanical response of the nanovesicles shows initial linear behavior and subsequent flattening corresponding to inward tether formation. We derive a quantitative model, including the competing effects of internal pressure and membrane bending, that corresponds well to these experimental observations. Our results are consistent with a bending modulus of the lipid bilayer of ∼14k b T. Surprisingly, we find that vesicle stiffness is pressure dominated for adherent vesicles under physiological conditions. Our experimental method and quantitative theory represents a robust approach to study the mechanics of nanoscale vesicles, which are abundant in biology, as well as being of interest for the rational design of liposomal vectors for drug delivery.

We report a new and general method, in situ growth, for designing self-assembled protein-polymer nanovesicles for intracellular protein delivery.In situ polymerization of a water-soluble monomer from a protein attached with a polymerization initiator yields amphiphilic protein conjugates of a water-insoluble polymer. These conjugates can in situ self-assemble into nanostructures with tunable morphologies from spheres to vesicles. Interestingly, an exogenous protein can be in situ encapsulated inside protein-polymer nanovesicles for enhanced intracellular protein delivery. The in situ growth method may open up new opportunities for designing a variety of self-assembled protein-polymer nanostructures tailored to specific applications.

On the basis of host-guest interactions, this study reported a kind of linear-hyperbranched supramolecular amphiphile and its assembled vesicles for the combined achievement of drug encapsulation and DNA delivery. Amine-attached β-cyclodextrin-centered hyperbranched polyglycerol and linear adamantane-terminated octadecane were arranged to spontaneously interlink together and then self-assemble into nanoscale vesicles. As the model of a hydrophilic agent, DOX·HCl was demonstrated to be readily loaded into the hollow cavity of the vesicles. The drug release pattern could be controlled by adjusting the environmental acidity, favoring the intracellularly fast drug liberation in response to the cellular lysosomal microenvironment. The nanovesicles displayed superior serum-tolerant transgene ability and significantly lower cytotoxicity compared to those of PEI25K, the gold standard of gene delivery vectors. The drug-loaded nanovesicle can co-deliver DNA payloads into cells and allow the preferable accumulation of two payloads in nuclei. The drug encapsulation was found to have little influence on the transfection. This co-delivery vehicle presents a good example of rational design of cationic supramolecular vesicles for stimulus-responsive drug/DNA transport.

A series of poly(ethylene glycol) methyl ether acrylate-block-poly(L-lysine)-block-poly(L-histidine) [p(PEGA)30-b-p(Lys)25-b-p(His)n] (n = 25, 50, 75, 100) triblock copolypeptides were designed and synthesized for tumoral pH-responsive intracellular release of anticancer drug doxorubicin hydrochloride (Dox). The tumoral acidic pH-responsive hybrid vesicles fabricated were stable at physiological pH 7.4 and could gradually destabilize in acidic pH as a result of pH-induced swelling of the p(His) block. The blank vesicles were nontoxic over a wide concentration range (0.01-100 μg/mL) in normal cell lines. The tumor acidic pH responsiveness of these vesicles was exploited for intracellular delivery of Dox. Vesicles efficiently encapsulated Dox, and pH-induced destabilization resulted in the controlled and sustained release of Dox in CT26 murine cancer cells, and dose-dependent cytotoxicity. The tumor-specific controlled release Dox from vesicles demonstrates this system represents a promising theranostic agent for tumor-targeted delivery.

Drug delivery systems that can be employed to load anticancer drugs and release them triggered by a specific stimulus, such as glutathione, are of great importance in cancer therapy. In this study, supramolecular porphysome nanovesicles that were self-assembled by amphiphilic porphyrin derivatives were successfully constructed, mainly driven by the π-π stacking, hydrogen bonding, and hydrophobic interactions, and were used as carriers of anticancer drugs. The nanovesicles are monodispersed in shape and uniform in size. The drug loading and in vitro drug release investigations indicate that these nanovesicles are able to encapsulate doxorubicin (DOX) to achieve DOX-loaded nanovesicles, and the nanovesicles could particularly release the loaded drug triggered by a high concentration of glutathione (GSH). More importantly, the drug release in cancer cells could be monitored by fluorescent recovery of the porphyrin derivative. Cytotoxicity experiments show that the DOX-loaded nanovesicles possess comparable therapeutic effect to cancer cells as free DOX. This study presents a new strategy in the fabrication of versatile anticancer drug nanocarriers with stimuli-responsive properties. Thus, the porphysome nanovesicles demonstrated here might offer an opportunity to bridge the gap between intelligent drug delivery systems and imaging-guided drug release.

Near-infrared fluorescent nanovesicles were prepared by self-assembly of block copolymer hydrophilic poly(ethylene glycol) boron-dipyrromethenes in aqueous solution. The fluorescence enhancement induced by dissociation of nanovesicles could be used as a smart imaging and diagnostic tool. This nanovesicle could encapsulate the antitumor drug, and provide a powerful platform for imaging-guided tumor-specific drug delivery and therapy.