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.

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.

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.

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.

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.

Fabrication of biodegradable composite microneedles based on calcium sulfate and gelatin for transdermal delivery of insulin.

To reduce the inconvenience and pain of subcutaneous needle injection, the calcium sulfate and gelatin biodegradable composite microneedle patches with high aspect-ratio microneedles (MNs) and a flexible substrate have been developed. The microneedles with an aspect-ratio approximate 6:1 exhibit excellent mechanical property which can achieve 0.4N for each needle. The cross-section views show the inside of microneedles that have abundant pores and channels which offer potential for different drug-release profiles. The preparation procedures, degradable property for the biodegradable composite microneedle patches are described in the paper. Insulin, the drug to control blood glucose levels in diabetic patients, has been embedded into the biodegradable composite MNs. The hypoglycemic effect for transdermal delivery of insulin is studied using diabetic Sprague-Dawley (SD) rats as models in vivo. After transdermal administration to the diabetic rats, the released insulin from biodegradable composite MNs exhibit an obvious and effective hypoglycemic effect for longer time compared with that of subcutaneous injection route. This work suggests that biodegradable composite MNs containing of insulin have a potential application in diabetes treatment via transdermal ingestion.

A composite hydrogel system containing glucose-responsive nanocarriers for oral delivery of insulin.

Development of an oral delivery strategy for insulin therapeutics has drawn much attention in recent years. In this study, a glucose-responsive nanocarriers for loading of insulin has been prepared firstly. The resultant nanocarriers exhibited relative low cytotoxicity against Caco-2 cells and excellent stability against protein solution. The insulin release behaviors were evaluated triggered by pH and glucose in vitro. In order to enhance the oral bioavailability of insulin, the insulin-loaded glucose-responsive nanocarriers were further encapsulated into a three-dimensional (3D) hyaluronic acid (HA) hydrogel environment for overcoming multiple barriers and providing multi-protection for insulin during the transport process. The hypoglycemic effect for oral delivery of insulin was studied in vivo. After oral administration to the diabetic rats, the released insulin from hydrogel systems containing insulin-loaded glucose-responsive nanocarriers exhibited an effective hypoglycemic effect for longer time compared with insulin-loaded nanocarriers.