Regulation of Two-Dimensional Platelet Micelles with Tunable Core Composition Distribution via Coassembly Seeded Growth Approach.

Seeded growth termed "living" crystallization-driven self-assembly (CDSA) has been identified as a powerful method to create one- or two-dimensional nanoparticles. Epitaxial crystallization is usually regarded as the growth mechanism for the formation of uniform micelles. From this perspective, the unimer depositing rate is largely related to the crystallization temperature, which is a key factor to determine the crystallization rate and regulate the core composition distribution among nanoparticles. In the present work, the coassembly of two distinct crystallizable polymers is explored in detail in a one-pot seeded growth protocol. Results have shown that polylactone containing a larger number of methylene groups (-CH2-) in their repeating units such as poly(η-octalactone) (POL) has a faster crystallization rate compared to poly(ε-caprolactone) (PCL) with a smaller number of -CH2- at ambient temperature (25 °C), thus a block or blocky platelet structure with heterogeneous composition distribution is formed. In contrast, when the crystallization temperature decreases to 4 °C, the difference of crystallization rate between both cores become negligible. Consequently, a completely random component distribution within 2D platelets is observed. Moreover, we also reveal that the core component of seed micelles is also paramount for the coassembly seeded growth, and a unique structure of flower-like platelet micelle is created from the coassembly of PCL/POL using POL core-forming seeds. This study on the formation of platelet micelles by one-pot seeded growth using two crystallizable components offers a considerable scope for the design of 2D polymer nanomaterials with a controlled core component distribution.

Biodegradable Lipid-Modified Poly(Guanidine Thioctic Acid)s: A Fortifier of Lipid Nanoparticles to Promote the Efficacy and Safety of mRNA Cancer Vaccines.

Lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics have emerged with promising potentials in the fields of infectious diseases, cancer vaccines, and protein replacement therapies; however, their therapeutic efficacy and safety can still be promoted by the optimization of LNPs formulations. Unfortunately, current LNPs suffer from increased production of reactive oxygen species during translation, which leads to a decreased translation efficiency and the onset of inflammation and other side effects. Herein, we synthesize a lipid-modified poly(guanidine thioctic acid) polymer to fabricate novel LNPs for mRNA vaccines. The acquired G-LNPs significantly promote the translation efficiency of loaded mRNA and attenuate inflammation after vaccination through the elimination of reactive oxygen species that are responsible for translational inhibition and inflammatory responses. In vivo studies demonstrate the excellent antitumor efficacy of the G-LNPs@mRNA vaccine, and two-dose vaccination dramatically increases the population and infiltration of cytotoxic T cells due to the intense antitumor immune responses, thus generating superior antitumor outcomes compared with the mRNA vaccine prepared from traditional LNPs. By synergy with immune checkpoint blockade, the tumor inhibition of G-LNPs@mRNA is further boosted, indicating that G-LNPs-based mRNA vaccines will be powerful and versatile platforms to combat cancer.

2D Hierarchical Microbarcodes with Expanded Storage Capacity for Optical Multiplex and Information Encryption.

The design of nanosegregated fluorescent tags/barcodes by geometrical patterning with precise dimensions and hierarchies could integrate multilevel optical information within one carrier and enhance microsized barcoding techniques for ultrahigh-density optical data storage and encryption. However, precise control of the spatial distribution in micro/nanosized matrices intrinsically limits the accessible barcoding applications in terms of material design and construction. Here, crystallization forces are leveraged to enable a rapid, programmable molecular packing and rapid epitaxial growth of fluorescent units in 2D via crystallization-driven self-assembly. The fluorescence encoding density, scalability, information storage capacity, and decoding techniques of the robust 2D polymeric barcoding platform are explored systematically. These results provide both a theoretical and an experimental foundation for expanding the fluorescence storage capacity, which is a longstanding challenge in state-of-the-art microbarcoding techniques and establish a generalized and adaptable coding platform for high-throughput analysis and optical multiplexing.

Precise Control of Two-Dimensional Hexagonal Platelets via Scalable, One-Pot Assembly Pathways Using Block Copolymers with Crystalline Side Chains.

Crystallization-driven self-assembly (CDSA) of block copolymers (BCPs) in selective solvents provides a promising route for direct access to two-dimensional (2D) platelet micelles with excellent uniformity, although significant limitations also exist for this robust approach, such as tedious, multistep procedures, and low yield of assembled materials. Herein, we report a facile strategy for massively preparing 2D, highly symmetric hexagonal platelets with precise control over their dimensions based on BCPs with crystalline side chains. Mechanistic studies unveiled that the formation of hexagonal platelets was subjected to a hierarchical self-assembly process, involving an initial stage of formation of kinetically trapped spheres upon cooling driven by solvophobic interactions, and a second stage of fusion of such spheres to the 2D nuclei to initiate the lateral growth of hexagonal platelets via sequential particle attachments driven by thermodynamically ordered reorganization of the BCP upon aging. Moreover, the size of the developed 2D hexagonal platelets could be finely regulated by altering the copolymer concentration over a broad concentration range, enabling scale-up to a total solids concentration of at least 6% w/w. Our work reveals a new mechanism to create uniform 2D core-shell nanoparticles dictated by crystallization and particle fusion, while it also provides an alternative facile strategy for the design of soft materials with precise control of their dimensions, as well as for the scalability of the derived nanostructures.

Tuning the Functionality of Self-Assembled 2D Platelets in the Third Dimension.

The decoration of 2D nanostructures using heteroepitaxial growth is of great importance to achieve functional assemblies employed in biomedical, electrical, and mechanical applications. Although the functionalization of polymers before self-assembly has been investigated, the exploration of direct surface modification in the third dimension from 2D nanostructures has, to date, been unexplored. Here, we used living crystallization-driven self-assembly to fabricate poly(ε-caprolactone)-based 2D platelets with controlled size. Importantly, surface modification of the platelets in the third dimension was achieved by using functional monomers and light-induced polymerization. This method allows us to selectively regulate the height and fluorescence properties of the nanostructures. Using this approach, we gained unprecedented spatial control over the surface functionality in the specific region of complex 2D platelets.

Understanding the Seeded Heteroepitaxial Growth of Crystallizable Polymers: The Role of Crystallization Thermodynamics.

Seeded heteroepitaxial growth is a "living" crystallization-driven self-assembly (CDSA) method that has emerged as a promising route to create uniform segmented nanoparticles with diverse core chemistries by using chemically distinct core-forming polymers. Our previous results have demonstrated that crystallization kinetics is a key factor that determines the occurrence of heteroepitaxial growth, but an in-depth understanding of controlling heteroepitaxy from the perspective of crystallization thermodynamics is yet unknown. Herein, we select crystallizable aliphatic polycarbonates (PxCs) with a different number of methylene groups (xCH2, x = 4, 6, 7, 12) in their repeating units as model polymers to explore the effect of lattice match and core compatibility on the seeded growth behavior. Seeded growth of PxCs-containing homopolymer/block copolymer blend unimers from poly(ε-caprolactone) (PCL) core-forming seed platelet micelles exhibits distinct crystal growth behavior at subambient temperatures, which is governed by the lattice match and core compatibility. A case of seeded growth with better core compatibility and a smaller lattice mismatch follows epitaxial growth, where the newly created crystal domain has the same structural orientation as the original platelet substrate. In contrast, a case of seeded growth with better core compatibility but a larger lattice mismatch shows nonepitaxial growth with less-defined crystal orientations in the platelet plane. Additionally, a case of seeded growth with poor core compatibility and larger lattice mismatch results in polydisperse platelet micelles, whereby crystal formation is not nucleated from the crystalline substrate. These findings reveal important factors that govern the specific crystal growth during a seeded growth approach by using compositionally distinct cores, which would further guide researchers in designing 2D segmented materials via polymer crystallization approaches.

Uniform segmented platelet micelles with compositionally distinct and selectively degradable cores.

The creation of nanoparticles with controlled and uniform dimensions and spatially defined functionality is a key challenge. The recently developed living crystallization-driven self-assembly (CDSA) method has emerged as a promising route to one-dimensional (1D) and 2D core-shell micellar assemblies by seeded growth of polymeric and molecular amphiphiles. However, the general limitation of the epitaxial growth process to a single core-forming chemistry is an important obstacle to the creation of complex nanoparticles with segmented cores of spatially varied composition that can be subsequently exploited in selective transformations or responses to external stimuli. Here we report the successful use of a seeded growth approach that operates for a variety of different crystallizable polylactone homopolymer/block copolymer blend combinations to access 2D platelet micelles with compositionally distinct segmented cores. To illustrate the utility of controlling internal core chemistry, we demonstrate spatially selective hydrolytic degradation of the 2D platelets-a result that may be of interest for the design of complex stimuli-responsive particles for programmed-release and cargo-delivery applications.

Uniform Two-Dimensional Crystalline Platelets with Tailored Compositions for pH Stimulus-Responsive Drug Release.

Two-dimensional, size-tunable, water-dispersible particle micelles with spatially defined chemistries can be obtained by using "living" crystallization-driven self-assembly (CDSA) approach. Nevertheless, a major obstacle of crystalline particles in drug delivery application is the difficulty in accessing to cargo within crystalline cores. In the present work, we design four different types of biocompatible two-dimensional platelets with a crystalline poly(ε-caprolactone) (PCL) core, a hydrophobic poly(4-vinylprydine) (P4VP) segment, and a water dispersible poly(N,N-dimethyl acrylamide) (PDMA) block in ethanol by seeded growth method. Transferring those uniform platelets with tailored compositions to an aqueous solution in the presence of a hydrophobic drug leads to efficient encapsulation of the cargo in the P4VP segments via hydrophobic interactions. These drug-loaded platelets exhibit pH-responsive release behavior in aqueous media due to the protonated-deprotonated process of P4VP blocks in acidic and neutral solutions. This work provides initial insight into biocompatible PCL platelets with low dispersity and precise chemistry control in stimulus-responsive drug delivery fields.

Block copolymer@ZIF-8 nanocomposites as a pH-responsive multi-steps release system for controlled drug delivery.

Developing the hybrid nanosystems for controlled drug release is still a challenging task. In this work, pH-responsive core-shell nanocomposites have been prepared by the growth of zeolitic imidazolate framework-8 (ZIF-8) on the surface of polymeric aggregates self-assembled from poly(ε-caprolactone)-block-poly (quaternized vinylbenzyl chloride/bipyridine) (PCL-b-q(PVBC/BPy), BCP for short) in water. The core of the micelles or the inner cavity of vesicles serves as the drug storage reservoir for the doxorubicin hydrochloride (DOX) and the ZIF-8 shells act as the gatekeepers to prevent drug premature release at physiological environment. Upon pH stimulus, the core-shell nanocomposites (BCP@ZIF-8) show a retarded drug release behavior compared with DOX-loaded polymeric aggregates counterparts (without the shell of ZIF-8). Moreover, the as-prepared nanocomposites perform good biocompatibility towards MCF-7 cell. Meanwhile, the DOX-loaded BCP@ZIF-8 nanocomposites present lower cytotoxicity compared with DOX-loaded BCP and free DOX. The confocal microscopy study shows the core-shell nanocomposites could be efficiently internalized by cancer cells, and the loaded DOX could be successfully released under acidic intracellular environment. The above result shows that the core-shell nanocomposite could be a promising candidate for pH-responsive drug delivery system in the cancer therapy.

Glucose- and pH-Responsive Supramolecular Polymer Vesicles Based on Host-Guest Interaction for Transcutaneous Delivery of Insulin.

Smart insulin delivery platforms having the ability of mimicking pancreatic cells are highly expected for diabetes treatment. Herein, a smart glucose-sensitive insulin delivery platform on the basis of transcutaneous microneedles has been designed. The as-prepared microneedles are composed of glucose- and pH-responsive supramolecular polymer vesicles (PVs) as the drug storage and water soluble polymers as the matrix. The well-defined PVs are constructed from the host-guest inclusion complex between water-soluble pillar[5]arene (WP5) with pH-responsiveness and paraquat-ended poly(phenylboronic acid) (PPBA-G) with glucose-sensitivity. The drug-loaded PVs, including insulin and glucose oxidase (GOx) can quickly respond to elevated glucose level, accompanied by the disassociation of PVs and fast release of encapsulated insulin. Moreover, the insulin release rate is further accelerated by GOx, which generates gluconic acid at high glucose levels, thus decreasing the local pH. Therefore, the host-guest interaction between WP5 and PPBA-G is destroyed and a total structure disassociation of PVs takes place, contributing to a fast release of encapsulated insulin. The in vivo insulin delivery to diabetic rats displays a quick response to hyperglycemic levels and then can fast regulate the blood glucose concentrations to normal levels, which demonstrates that the obtained smart insulin device has a highly potential application in the treatment of diabetes.

Interfacial self-assembly of amphiphilic conjugated block copolymer into 2D nanotapes.

In the present work, the evaporation-induced interfacial self-assembly behavior of an amphiphilic conjugated polymer, poly(3-hexylthiophene)-b-poly(acrylic acid) (P3HT-b-PAA), at the oil-water interface is explored. Novel 2D nanotapes of P3HT-b-PAA are prepared via the interfacial self-assembly. It is inferred that P3HT segments adopt a special conformation at the oil-water interface, which facilitates the packing of alkyl side chains and π-π interaction. The UV-vis spectrum further confirms that the ordering degree of P3HT segments is increased while transmission IR and Raman spectroscopic studies suggest that the P3HT chains adopt a more planar conformation at the oil-water interface. It is proposed that the formation of the nanotapes is driven by the ordered packing of the P3HT chains at the oil-water interface. Finally, the packing model of the P3HT chains inside the nanotapes is roughly proposed.

Upper critical solution temperature polymer-grafted hollow mesoporous silica nanoparticles for near-infrared-irradiated drug release.

Near-infrared (NIR) irradiation responsive drug delivery systems have many advantages, which have attracted extensive interest from researchers. In this study, a NIR-triggered drug release system was established by grafting upper critical solution temperature (UCST) polymers on the surface of hollow mesoporous silica nanoparticles (HMSNs) followed by treatment with the photothermal conversion agent indocyanine green (ICG). The as-prepared UCST polymers showed the clearing temperature of 45 °C, which were advantageous to serve as gatekeepers in the physiological environment (37 °C). Under NIR irradiation, the temperature of the solution was elevated above the clearing point due to the presence of ICG; consequently, the collapsed UCST polymer chains became more hydrophilic; this resulted in the exposure of the mesoporous channels of the HMSNs and achievement of a burst drug release. Moreover, this NIR-responsive delivery system showed good biocompatibility and high anticancer efficiency towards the MCF-7 cancer cells upon exposure to NIR irradiation. In addition, a synergistic effect of thermal and chemo treatment has been achieved by the application of NIR irradiation since cancer cells are more vulnerable to high temperatures than normal cells.

Reactive Oxygen Species Synergistic pH/H2O2-Responsive Poly(l-lactic acid)-block-poly(sodium 4-styrenesulfonate)/Citrate-Fe(III)@ZIF-8 Hybrid Nanocomposites for Controlled Drug Release.

Combination of photodynamic therapy and chemotherapeutic drugs is a promising strategy to achieve enhanced anticancer effect. In this study, a novel reactive oxygen species (ROS) synergistic pH/H2O2-responsive nanocomposite has been prepared from the self-assembly of poly(l-lactic acid)-block-poly(sodium 4-styrenesulfonate) in aqueous solution, followed by addition of ferric citrate (Cit-Fe(III)) through electrostatic interaction and growing ZIF-8 among the surface of the particles. Upon H2O2 and visible light stimuli, efficient ROS such as hydroxyl radicals (•OH) and sulfate radicals (SO4•-) can be generated through the catalyst of Cit-Fe(III). Meanwhile, sulfonate-containing polymeric vesicles are disassembled through oxidization by ROS, and the encapsulated doxorubicin (DOX) will gradually diffuse into the ZIF-8 (one type of metal-organic framework, MOF) channels. The gatekeepers, ZIF-8, will collapse only under low pH condition, and a burst drug release is achieved. In the presence of H2O2 and pH stimuli upon visible light exposure, the prepared DOX-loaded nanocomposite exhibits good selectivity for both generating ROS and releasing drug in tumor cell instead of normal cell. The merits of nanocomposites such as good biocompatibility and especially the synergistic effect of chemo-photodynamic therapy make the material a highly promising candidate for drug delivery system in chemo-photodynamic therapy.

Redox and pH responsive polymeric vesicles constructed from a water-soluble pillar[5]arene and a paraquat-containing block copolymer for rate-tunable controlled release.

Herein, for rate-tunable controlled release, pH and redox dual responsive polymeric vesicles were constructed based on host-guest interaction between a water soluble pillar[5]arene (WP5) and a paraquat-containing block copolymer (BCP) in water. The yielding polymeric vesicles can be further applied in the controlled release of a hydrophilic model drug, doxorubicin hydrochloride (DOX). The drug release rate is regulated depending on the type of single stimulus or the combination of two stimuli. Meanwhile, DOX-loaded polymeric vesicles present anticancer activity in vitro comparable to free DOX under the studied conditions, which may be important for applications in the therapy of cancers as a controlled-release drug carrier.

Supramolecular chemotherapeutic drug constructed from pillararene-based supramolecular amphiphile.

Based on the host-guest interaction between a CPT-conjugated prodrug amphiphile (CPT-ss-Py) and a water-soluble pillar[5]arene (P5), a GSH-responsive supramolecular chemotherapeutic drug (P5⊃CPT-ss-Py) was fabricated. Through this supramolecular formulation, internalization and anticancer efficacy were greatly increased.

Preparation and characterization of casein-carrageenan conjugates and self-assembled microcapsules for encapsulation of red pigment from paprika.

This study aimed to investigate the optimum preparation condition of casein- carrageenan conjugate by ultrasonic Maillard dry treatment. The stable microcapsule was self-assembly prepared by the conjugates applied to protect red pigment from paprika. The optimum substrate ratio of Cas-Ca is 1:2, the reaction time and temperature were 24 h and 60 °C. Finally, the optimal degree of grafting reached 78.05%. Conjugation with carrageenan could further enhance solubility and emulsifying properties of casein. Glycosylation self-assembly nanoparticles were prepared with ultrasonic treatment, and the stability of the nanoparticles were excellent. Cas-Ca was effectively used to encapsulate PRP, and the PRP and PRP-microcapsule were stored for six days under the condition of high temperature, lighting, and food additives to observe the PRP retention rate. These results indicated the outstanding protective effect of microcapsule on PRP. Cas-Ca could be used as an effective carrier of PRP. They could effectively control release behavior in simulated gastrointestinal fluid. Cas-Ca microcapsule was disintegrated and released slowly within 3 h in simulated gastric fluid, but released rapidly within 1 h in intestinal environments, and the total release rate reached 76.6%.

Glucose- and H2O2-Responsive Polymeric Vesicles Integrated with Microneedle Patches for Glucose-Sensitive Transcutaneous Delivery of Insulin in Diabetic Rats.

Herein, a dual-responsive insulin delivery device by integrating glucose- and H2O2-responsive polymeric vesicles (PVs) with transcutaneous microneedles (MNs) has been designed. This novel microneedle delivery device achieves a goal of fast response, excellent biocompatibility, and painless administration. The PVs are self-assembled from a triblock copolymer including poly(ethylene glycol), poly(phenylboronic acid) (glucose-sensitive block), and poly(phenylboronic acid pinacol ester) (H2O2-sensitive block). After loading with insulin and glucose oxidase (GO x), the drug-loaded PVs display a basal insulin release as well as a promoted insulin release in response to hyperglycemic states. The insulin release rate responds quickly to elevated glucose and can be further promoted by the incorporated GO x, which will generate the H2O2 at high glucose levels and further break the chemical links of phenylboronic acid pinacol ester group. Finally, the transdermal delivery of insulin to the diabetic rats ((insulin + GO x)-loaded MNs) presents an effective hypoglycemic effect compared to that of subcutaneous injection or only insulin-loaded MNs, which indicates the as-prepared MNs insulin delivery system could be of great importance for the applications in the therapy of diabetes.

Photo/pH-controlled host-guest interaction between an azobenzene-containing block copolymer and water-soluble pillar[6]arene as a strategy to construct the "compound vesicles" for controlled drug delivery.

Herein, dual stimuli-responsive compound vesicles were constructed based on host-guest interaction between a water-soluble pillar[6]arene (WP6) and an amphiphilic azobenzene-containing block copolymers (BCP). Reversible morphological transformation between compound vesicles and solid aggregates was achieved by repeated pH- and photo-stimuli. These compound vesicles were then applied in the controlled release of water-soluble anticancer drug, doxorubicin hydrochloride (DOX ·â€¯HCl). Upon external stimuli, the DOX ·â€¯HCl displayed a faster release rate than that without stimuli. Moreover, the compound vesicles showed an excellent cytocompatibility toward the human breast cancer cells (Michigan Cancer Foundation-7, MCF-7), and the drug-loaded compound vesicles exhibited lower cytotoxicity than free drug. The drug-loaded compound vesicles could be taken up by MCF-7 cells and can release the DOX ·â€¯HCl in cancer cells due to the acid environment, which was important for applications in the therapy of cancers as a controlled-release drug carrier.

Transdermal delivery of insulin with bioceramic composite microneedles fabricated by gelatin and hydroxyapatite.

The organic-inorganic bioceramic composite microneedles (MNs) were prepared from hydroxyapatite (Hap) and gelatin (Gel) via a template method. The resultant hydroxyapatite and gelatin composite MNs exhibited low cytotoxicity and excellent mechanical properties. After transdermal administration to the diabetic rats, the insulin could be released from bioceramic composite MNs. An obvious and effective hypoglycemic effect could be obtained compared with that of subcutaneous injection route. This work suggests that bioceramic composite MNs containing of insulin have a potential application in diabetes treatment via transdermal ingestion.

Surfactant-Mediated Crystallization-Driven Self-Assembly of Crystalline/Ionic Complexed Block Copolymers in Aqueous Solution.

A series of crystalline/ionic complexed block copolymers (BCPs) with various compositions have been prepared by sequential reactions. The BCPs with different hydrophilic fractions can self-assemble into various morphologies, such as spindlelike, rodlike, and spherical micelles with different crystallinity of the core. Bis(2-ethylhexyl) sulfosuccinate sodium salt (AOT) is added as a surfactant to induce the morphological transition of BCPs in aqueous media. The introduced AOT can be tightly bound to the cationic units, and a water-insoluble unit in the corona forms, leading to a reduced tethering density. Consequently, morphological variety changing from rods to platelets to fibril to dendrite-like micelles can be observed.