Complex Energy Landscapes of Self-Assembled Vesicles.

The field of supramolecular chemistry has witnessed tremendous progress in bringing the system away from equilibrium for traditionally inaccessible structures and functions. Vesicular assemblies with complex energy landscapes and pathways, which are reminiscent of diverse cellular vesicles like exosomes, remain exceedingly rare. Here, relying on the activation of oligo(ethylene glycol) (OEG) interdigitation and the encoded conformational freedom in monodisperse Janus dendrimers, we reveal a rich landscape and a pathway selection of distinct vesicles. The interdigitation can be selectively switched on and off using temperature ramps, and the critical temperatures can be further determined by molecular design. Our findings suggest that synthetic vesicles, with different energy states and unexpected transition pathways, emulate dynamic cellular vesicles in nature. We anticipate that vesicles with an activated OEG corona conformation will open new routes for nanomedicine and advanced materials.

Fabrication of Self-Propelled Micro- and Nanomotors Based on Janus Structures.

Delicate molecular and biological motors are tiny machines capable of achieving numerous vital tasks in biological processes. To gain a deeper understanding of their mechanism of motion, researchers from multiple backgrounds have designed and fabricated artificial micro- and nanomotors. These nano-/microscale motors can self-propel in solution by exploiting different sources of energy; thus showing tremendous potential in widespread applications. As one of the most common motor systems, Janus motors possess unique asymmetric structures and integrate different functional materials onto two sides. This review mainly focuses on the fabrication of different types of micro- and nanomotors based on Janus structures. Furthermore, some challenges still exist in the implementation of Janus motors in the biomedical field. With such common goals in mind, it is expected that the elaborate and multifunctional design of Janus motors will overcome their challenges in the near future.

Thermogelling polymer-platinum(IV) conjugates for long-term delivery of cisplatin.

In this study, we suggest a novel strategy of constituting an in situ-formed hydrogel composed of polymer-platinum(IV) conjugate to realize a long-term delivery of cisplatin. A unique conjugate was designed and synthesized by covalent linking of Pt(IV) complex to the hydrophobic end of two methoxyl poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-PLA) copolymer chains, resulting in the formation of Bi(mPEG-PLA)-Pt(IV). The conjugate could self-assemble into micelles in water, and its concentrated solution exhibited a thermoreversible sol-gel transition and formed a semisolid thermogel at body temperature. The incorporation of the cisplatin analogue Pt(IV) prodrug into the conjugate had a significant influence on its thermogelling properties and the conjugate thermogelation was attributed to the micellar aggregation. In vitro release experiments of Pt(IV)-conjugated thermogel showed that the platinum release lasted as long as two months. Furthermore, we demonstrated that the Pt(IV) prodrug was released mainly in the form of micelles and micellar aggregates from the gel depot. Compared with free cisplatin, the formation of conjugate micelles led to the enhanced in vitro cytotoxicity against cancer cells due to the effective accumulation into cells via endocytosis.

Microfluidic Design of Streamlined Alginate Hydrogel Micromotors with Run and Tumble Motion Patterns.

Autonomous micromotors demonstrate remarkable advancements in biomedical applications. A noteworthy example is streamlined motors, which display enhanced movement efficiency with low fluid-resistance. However, existing streamlined motors, primarily constructed from inorganic materials, present challenges due to their complex fabrication procedures and lack of a soft interface for interaction with biological systems. Herein, a novel design of biodegradable streamlined alginate hydrogel micromotors with a teardrop shape by microfluidics is introduced. The platform enables the high-throughput fabrication of monodisperse micromotors with varied dimensions. By incorporating Pt-coated Fe3 O4 nanoparticles, micromotors are equipped with dual capabilities of catalytic propulsion and accurate magnetic guidance. Through precisely tuning the localization regions of catalysts within the micromotors, the streamlined hydrogel micromotors not only exhibit enhanced propelling efficiency, but also accomplish distinct motion patterns of run and tumble. The design provides insights for developing advanced micromotors capable of executing intricate tasks across diverse application scenarios.

Morphogenesis of starfish polymersomes.

The enhanced membrane stability and chemical versatility of polymeric vesicles have made them promising tools in micro/nanoreactors, drug delivery, cell mimicking, etc. However, shape control over polymersomes remains a challenge and has restricted their full potential. Here we show that local curvature formation on the polymeric membrane can be controlled by applying poly(N-isopropylacrylamide) as a responsive hydrophobic unit, while adding salt ions to modulate the properties of poly(N-isopropylacrylamide) and its interaction with the polymeric membrane. Polymersomes with multiple arms are fabricated, and the number of arms could be tuned by salt concentration. Furthermore, the salt ions are shown to have a thermodynamic effect on the insertion of poly(N-isopropylacrylamide) into the polymeric membrane. This controlled shape transformation can provide evidence for studying the role of salt ions in curvature formation on polymeric membranes and biomembranes. Moreover, potential stimuli-responsive non-spherical polymersomes can be good candidates for various applications, especially in nanomedicine.

Adaptive insertion of a hydrophobic anchor into a poly(ethylene glycol) host for programmable surface functionalization.

Covalent and non-covalent molecular binding are two strategies to tailor surface properties and functions. However, the lack of responsiveness and requirement for specific binding groups makes spatiotemporal control challenging. Here, we report the adaptive insertion of a hydrophobic anchor into a poly(ethylene glycol) (PEG) host as a non-covalent binding strategy for surface functionalization. By using polycyclic aromatic hydrocarbons as the hydrophobic anchor, hydrophilic charged and non-charged functional modules were spontaneously loaded onto PEG corona in 2 min without the assistance of any catalysts and binding groups. The thermodynamically favourable insertion of the hydrophobic anchor can be reversed by pulling the functional module, enabling programmable surface functionalization. We anticipate that the adaptive molecular recognition between the hydrophobic anchor and the PEG host will challenge the hydrophilic understanding of PEG and enhance the progress in nanomedicine, advanced materials and nanotechnology.

Generating biomembrane-like local curvature in polymersomes via dynamic polymer insertion.

Biomembrane curvature formation has long been observed to be essential in the change of membrane morphology and intracellular processes. The significant importance of curvature formation has attracted scientists from different backgrounds to study it. Although magnificent progress has been achieved using liposome models, the instability of these models restrict further exploration. Here, we report a new approach to mimic biomembrane curvature formation using polymersomes as a model, and poly(N-isopropylacrylamide) to induce the local curvature based on its co-nonsolvency phenomenon. Curvatures form when poly(N-isopropylacrylamide) becomes hydrophobic and inserts into the membrane through solvent addition. The insertion area can be fine-tuned by adjusting the poly(N-isopropylacrylamide) concentration, accompanied by the formation of new polymersome-based non-axisymmetric shapes. Moreover, a systematic view of curvature formation is provided through investigation of the segregation, local distribution and dissociation of inserted poly(N-isopropylacrylamide). This strategy successfully mimicks biomembrane curvature formation in polymersomes and a detailed observation of the insertion can be beneficial for a further understanding of the curvature formation process. Furthermore, polymer insertion induced shape changing could open up new routes for the design of non-axisymmetric nanocarriers and nanomachines to enrich the boundless possibilities of nanotechnology.

Leveraging synthetic particles for communication: from passive to active systems.

Communication is one of the most remarkable behaviors in the living world. It is an important prerequisite for building an artificial cell which can be considered as alive. Achieving complex communicative behaviors leveraging synthetic particles will likely fill the gap between artificial vesicles and natural counterpart of cells and allow for the discovery of new therapies in medicine. In this review, we highlight recent endeavors for constructing communication with synthetic particles by revealing the principles underlying the communicative behaviors. Emergent progress using active particles to achieve communication is also discussed, which resembles the dynamic and out-of-equilibrium properties of communication in nature.

Thermogel Loaded with Low-Dose Paclitaxel as a Facile Coating to Alleviate Periprosthetic Fibrous Capsule Formation.

Medical-grade silicones as implants have been utilized for decades. However, the postoperative complications, such as capsular formation and contracture, have not yet been fully controlled and resolved. The aim of the present study is to elucidate whether the capsular formation can be alleviated by local and sustained delivery of low-dose paclitaxel (PTX) during the critical phase after the insertion of silicone implants. A biocompatible and thermogelling poly(lactic acid- co-glycolic acid)- b-poly(ethylene glycol)- b-poly(lactic acid- co-glycolic acid) triblock copolymer was synthesized by us. The micelles formed by the amphiphilic polymers in water could act as a reservoir for the solubilization of PTX, a very hydrophobic drug. The concentrated polymer aqueous solution containing PTX exhibited a sol-gel transition upon heating and formed a thermogel depot at body temperature. In vitro release tests demonstrated that the entrapped microgram-level PTX displayed a sustained release manner up to 57 days without a significant initial burst effect. Customized silicone implants coated with the PTX-loaded thermogels at various drug concentrations were inserted into the pockets of the subpanniculus carnosus plane of rats. The histological observations performed 1 month postoperation showed that the sustained release of PTX with an appropriate dose significantly reduced the peri-implant capsule thickness, production and deposition of collagen, and expression of contracture-mediating factors compared with bare silicone implants. More importantly, such an optimum dose had an excellent repeatability for the suppression of the capsular formation. Therefore, this study provides a strategic foothold regarding the sustained release of low-dose PTX to alleviate fibrotic capsule formation after implantation, and the microgram-level PTX-loaded thermogel holds great potential as an "all-purpose antifibrosis coating" for veiling the surfaces of various implantable medical devices.

Sustained Codelivery of Cisplatin and Paclitaxel via an Injectable Prodrug Hydrogel for Ovarian Cancer Treatment.

The sustained release of both the hydrophilic drug and hydrophobic drug from one delivery system remains challenging in pharmaceutics and biomaterials science. The combination of hydrophilic cisplatin and hydrophobic paclitaxel (PTX) exhibits a clinical survival advantage compared with the individual drug therapy against various tumors such as ovarian cancer. In this study, a localized, long-term codelivery system of cisplatin and PTX was developed using an injectable and thermosensitive polymer-platinum(IV) conjugate hydrogel as the carrier. The thermosensitive Bi(mPEG-PLGA)-Pt(IV) (PtGel) conjugate was synthesized via covalently linking two mPEG-PLGA copolymers onto a Pt(IV) prodrug, and its concentrated aqueous solution exhibited a reversible sol-gel transition upon heating. Meanwhile, the core-corona micelles formed by the amphiphilic conjugates in water could serve as a reservoir for the solubilization of PTX, and thus an injectable binary drug-loaded hydrogel formulation was obtained. We also found that the introduction of PTX into the conjugate hydrogel decreased its sol-gel transition temperature and improved its gel strength. In vitro release experiments showed that both of the loaded drugs were released in a sustained manner for as long as 2.5 months, which was the longest combination delivery of these two drugs ever reported. In vitro cellular assays revealed that the dual-drug system exhibited a synergistic anticancer effect against ovarian cancer cells. Finally, using the SKOV-3 ovarian cancer xenograft mouse model, we demonstrated that a single injection of the PTX-loaded conjugate hydrogel system resulted in enhanced anticancer efficacy and significantly reduced the side effects, when compared with the multiple injections of the free drug combination.

Injectable and Thermosensitive Hydrogel Containing Liraglutide as a Long-Acting Antidiabetic System.

Diabetes, a global epidemic, has become a serious threat to public health. The present study is aimed at constructing an injectable thermosensitive PEG-polyester hydrogel formulation of liraglutide (Lira), a "smart" antidiabetic polypeptide, in the long-acting treatment of type 2 diabetes mellitus. A total of three thermosensitive poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) (PCGA-PEG-PCGA) triblock copolymers with similar molecular weights but different ε-caprolactone-to-glycolide (CL-to-GA) ratios were synthesized. The polymer aqueous solutions exhibited free-flowing sols at room temperature and formed in situ hydrogels at body temperature. While the different bulk morphologies, stabilities of aqueous solutions, and the varying in vivo persistence time of hydrogels in ICR mice were found among the three copolymers, all of the Lira-loaded gel formulations exhibited a sustained drug release manner in vitro regardless of CL-to-GA ratios. The specimen with a powder form in the bulk state, a stable aqueous solution before heating, and an appropriate degradation rate in vivo was selected as the optimal carrier to evaluate the in vivo efficacy. A single injection of the optimal gel formulation showed a remarkable hypoglycemic efficacy up to 1 week in diabetic db/db mice. Furthermore, three successive administrations of this gel formulation within one month significantly lowered glycosylated hemoglobin and protected islets of db/db mice. As a result, a promising once-weekly delivery system of Lira was developed, which not only afforded long-term glycemic control but also significantly improved patient compliance.

Sustained intravitreal delivery of dexamethasone using an injectable and biodegradable thermogel.

Delivery of therapeutic agents to posterior segment of the eyes is challenging due to the anatomy and physiology of ocular barriers and thus long-acting implantable formulations are much desired. In this study, a thermogelling system composed of two poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was developed as an injectable matrix for intravitreal drug delivery. The thermogel was prepared by mixing a sol and a precipitate of PLGA-PEG-PLGA triblock copolymers with different block ratios, among which a hydrophobic glucocorticoid, dexamethasone (DEX), was incorporated. The DEX-loaded thermogel was a low-viscous liquid at low temperature and formed a non-flowing gel at body temperature. The in vitro release rate of DEX from the thermogel could be conveniently modulated by varying the mixing ratio of the two copolymers. The long-lasting intraocular residence of the thermogel was demonstrated by intravitreal injection of a fluorescence-labeled thermogel to rabbits. Compared with a DEX suspension, the intravitreal retention time of DEX increased from a dozen hours to over 1week when being loaded in the thermogel. Additionally, intravitreal administration of the thermogel did not impair the morphology of retina and cornea. This study reveals that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for sustained delivery of bioactive agents into the eyes, and provides an alternative approach for treatment of posterior segment diseases.

In situ synthesis of silver-nanoparticles/bacterial cellulose composites for slow-released antimicrobial wound dressing.

Bacterial cellulose has attracted increasing attention as a novel wound dressing material, but it has no antimicrobial activity, which is one of critical skin-barrier functions in wound healing. To overcome such deficiency, we developed a novel method to synthesize and impregnate silver nanoparticles on to bacterial cellulose nanofibres (AgNP-BC). Uniform spherical silver nano-particles (10-30 nm) were generated and self-assembled on the surface of BC nano-fibers, forming a stable and evenly distributed Ag nanoparticles coated BC nanofiber. Such hybrid nanostructure prevented Ag nanoparticles from dropping off BC network and thus minimized the toxicity of nanoparticles. Regardless the slow Ag(+) release, AgNP-BC still exhibited significant antibacterial activities with more than 99% reductions in Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Moreover, AgNP-BC allowed attachment and growth of epidermal cells with no cytotoxicity emerged. The results demonstrated that AgNP-BC could reduce inflammation and promote wound healing.

Impregnation of silver sulfadiazine into bacterial cellulose for antimicrobial and biocompatible wound dressing.

Silver sulfadiazine (SSD) is a useful antimicrobial agent for wound treatment. However, recent findings indicate that conventional SSD cream has several drawbacks for use in treatments. Bacterial cellulose (BC) is a promising material for wound dressing due to its outstanding properties of holding water, strength and degradability. Unfortunately, BC itself exhibits no antimicrobial activity. A combination of SSD and BC is envisaged to form a new class of wound dressing with both antimicrobial activity and biocompatibility, which has not been reported to date. To achieve antimicrobial activity, SSD particles were impregnated into BC by immersing BC into SSD suspension after ultrasonication, namely SSD-BC. Parameters influencing SSD-BC impregnation were systematically studied. Optimized conditions of sonication time for no less than 90 min and the proper pH value between 6.6 and 9.0 were suggested. The absorption of SSD onto the BC nanofibrous network was revealed by XRD and SEM analyses. The SSD-BC membranes exhibited significant antimicrobial activities against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus evaluated by the disc diffusion method. In addition, the favorable biocompatibility of SSD-BC was verified by MTT colorimetry, epidermal cell counting method and optical microscopy. The results demonstrate the potential of SSD-BC membranes as a new class of antimicrobial and biocompatible wound dressing.