Tadpole-Like Polar Molecule Encapsulated in a Two-in-One Supramolecular Cage: Molecular Motion, Phase Transition and Ferroelectricity.

Molecule-inclusive closed cage compounds present a unique platform for molecular motion in an isolated environment. This study showcases the incorporation of a tadpole-like polar molecule (1-propyl-1H-imidazole, PIm) into a supramolecular cage formed by duad semicage p-tert-butylcalix[4]arene. The ferroelectric phase transition as well as the cage-confined motion of encapsulated PIm was studied in detail. The unusual quadrastable state of the PIm in the paraelectric phase allows for the modulation of dipolar polarization over a broad temperature/frequency range. This compound represents the first example of a clathrate molecular ferroelectric featuring a molecule-inclusive supramolecular cage, and it also contributes to the understanding of cage-confined molecular dynamics.

Self-adjuvanting polymeric nanovaccines enhance IFN production and cytotoxic T cell response.

Vaccines represent one of the most powerful and cost-effective innovations for controlling a wide range of infectious diseases caused by various viruses and bacteria. Unlike mRNA and DNA-based vaccines, subunit vaccines carry no risk of insertional mutagenesis and can be lyophilized for convenient transportation and long-term storage. However, existing adjuvants are often associated with toxic effect and reactogenicity, necessitating expanding the repertoire of adjuvants with better biocompatibility, for instance, designing self-adjuvating polymeric carriers. We herein report a novel subunit vaccine delivery platform constructed via in situ free radical polymerization of C7A (2-(Hexamethyleneimino) ethyl methacrylate) and acrylamide around the surface of individual protein antigens. Using ovalbumin (OVA) as a model antigen, we observed substantial increases in both diameter (∼70 nm) and surface potential (-1.18 mV) following encapsulation, referred to as n(OVA)C7A. C7A's ultra pH sensitivity with a transition pH around 6.9 allows for rapid protonation in acidic environments. This property facilitates crucial processes such as endosomal escape and major histocompatibility complex (MHC)-I-mediated antigen presentation, culminating in the substantial CD8+ T cell activation. Additionally, compared to OVA nanocapsules without the C7A components and native OVA without modifications, we observed heightened B cell activation within the germinal center, along with remarkable increases in serum antibody and cytokine production. It's important to note that mounting evidence suggests that adjuvant effects, particularly its targeted stimulation of type I interferons (IFNs), can contribute to advantageous adaptive immune responses. Beyond its exceptional potency, the nanovaccine also demonstrated robust formation of immune memory and exhibited a favorable biosafety profile. These findings collectively underscore the promising potential of our nanovaccine in the realm of immunotherapy and vaccine development.

Remodeling the Electronic Structure of Metallic Nickel and Ruthenium via Alloying in a Molecular Template for Sustainable Hydrogen Evolution.

The reasonably constructed high-performance electrocatalyst is crucial to achieve sustainable electrocatalytic water splitting. Alloying is a prospective approach to effectively boost the activity of metal electrocatalysts. However, it is a difficult subject for the controllable synthesis of small alloying nanostructures with high dispersion and robustness, preventing further application of alloy catalysts. Herein, we propose a well-defined molecular template to fabricate a highly dispersed NiRu alloy with ultrasmall size. The catalyst presents superior alkaline hydrogen evolution reaction (HER) performance featuring an overpotential as low as 20.6 ± 0.9 mV at 10 mA·cm-2. Particularly, it can work steadily for long periods of time at industrial-grade current densities of 0.5 and 1.0 A·cm-2 merely demanding low overpotentials of 65.7 ± 2.1 and 127.3 ± 4.3 mV, respectively. Spectral experiments and theoretical calculations revealed that alloying can change the d-band center of both Ni and Ru by remodeling the electron distribution and then optimizing the adsorption of intermediates to decrease the water dissociation energy barrier. Our research not only demonstrates the tremendous potential of molecular templates in architecting highly active ultrafine nanoalloy but also deepens the understanding of water electrolysis mechanism on alloy catalysts.

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity.

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Molecular rotators anchored on a rod-like anionic coordination polymer adhered by charge-assisted hydrogen bonds.

On the basis of variable-temperature single-crystal X-ray diffraction, variable-temperature/frequency dielectric analysis, variable-temperature solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, here we present a new model of crystalline supramolecular rotor (i-PrNHMe2)[CdBr3], where a conformationally flexible near-spherical (i-PrNHMe2)+ cation functions as a rotator and a rod-like anionic coordination polymer {[CdBr3]-}∞ acts as the stator, and the adhesion of them is realized by charge-assisted hydrogen bonds.

A confinement-regulated (H3C-NH3)+ ion as a smallest dual-wheel rotator showing bisected rotation dynamics.

On the basis of variable-temperature single-crystal X-ray diffraction, rotational energy barrier analysis, variable-temperature/frequency dielectric response, and molecular dynamics simulations, here we report a new crystalline supramolecular rotor (CH3NH3)(18-crown-6)[CuCl3], in which the (H3C-NH3)+ ion functions as a smallest dual-wheel rotator showing bisected rotation dynamics, while the host 18-crown-6 macrocycle behaves as a stator that is not strictly stationary. This study also provides a helpful insight into the dynamics of ubiquitous -CH3/-NH3 groups confined in organic or organic-inorganic hybrid solids.

Transdermally delivered tolerogenic nanoparticles induced effective immune tolerance for asthma treatment.

Induction of antigen-specific immune tolerance for the treatment of allergic or autoimmune diseases is an attractive strategy. Herein, we investigated the protective effect of a transdermal microneedle patch against allergic asthma by stimulating allergen-specific immune tolerance. We fabricated biodegradable tolerogenic nanoparticles (tNPs) that are loaded with a model allergen ovalbumin (OVA) and an immunomodulator rapamycin, and filled the tNPs into microneedle tips by centrifugation to form sustained-release microneedles. After intradermal immunization, the microneedles successfully delivered the cargos into the skin and sustainedly released them for over 96 h. Importantly, the microneedles induced allergen-specific regulatory T cells (Treg), decreased the levels of pro-inflammatory cytokines and antibodies while increased anti-inflammation cytokines, finally leading to restored immune homeostasis. The lung tissue analysis illustrated that the sustained-release microneedles significantly reduced the infiltration of eosinophils, decreased the accumulation of mucus and collagen, and significantly relived asthma symptoms. Our results suggested that the sustained-release microneedle-based transdermal delivery system can induce antigen-specific immune tolerance with improved compliance and efficacy, providing a new therapeutic strategy for the treatment of allergic and autoimmune diseases.

Co-delivery of oxaliplatin prodrug liposomes with Bacillus Calmette-Guérin for chemo-immunotherapy of orthotopic bladder cancer.

To reduce recurrence rate after transurethral resection of bladder tumor, long-term intravesical instillations of Bacillus Calmette-Guérin (BCG) and/or chemotherapeutic drugs is the standard treatment for non-muscle invasive bladder carcinoma. However, the main challenges of intravesical therapy, such as short retention time and poor permeability of drugs in the bladder, often require frequent and high-dose administrations, leading to significant adverse effects and financial burden for patients. Aiming at addressing these challenges, we developed a novel approach, in which the cell-penetrating peptide modified oxaliplatin prodrug liposomes and a low-dose BCG were co-delivered via a viscous chitosan solution (LRO-BCG/CS). LRO-BCG/CS addressed these challenges by significantly improving the retention capability and permeability of chemotherapy agents across the bladder wall. Then, oxaliplatin triggered the immunogenic cell death, and the combination of BCG simultaneously further activated the systemic anti-tumor immune response in the MB49 orthotopic bladder tumor model. As a result, LRO-BCG/CS demonstrated superior anti-tumor efficacy and prolonged the survival time of tumor-bearing mice significantly, even at relatively low doses of oxaliplatin and BCG. Importantly, this combinational chemo-immunotherapy showed negligible side effects, offering a promising and well-tolerated therapeutic strategy for bladder cancer patients.

An antigen self-assembled and dendritic cell-targeted nanovaccine for enhanced immunity against cancer.

The rise of nanotechnology has opened new horizons for cancer immunotherapy. However, most nanovaccines fabricated with nanomaterials suffer from carrier-related concerns, including low drug loading capacity, unpredictable metabolism, and potential systemic toxicity, which bring obstacles for their clinical translation. Herein, we developed an antigen self-assembled nanovaccine, which was resulted from a simple acryloyl modification of the antigen to induce self-assembly. Furthermore, a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid (Zol) were integrated or absorbed onto the nanoparticles (denoted as MEAO-Z) to intensify the immune response. The synthesized nanovaccine with a diameter of around 70 nm showed successful lymph node transportation, high dendritic cell internalization, promoted costimulatory molecule expression, and preferable antigen cross-presentation. In virtue of the above superiorities, MEAO-Z induced remarkably higher titers of serum antibody, stronger cytotoxic T lymphocyte immune responses and IFN-γ secretion than free antigen and adjuvants. In vivo, MEAO-Z significantly suppressed EG7-OVA tumor growth and prolonged the survival time of tumor-bearing mice. These results indicated the translation promise of our self-assembled nanovaccine for immune potentiation and cancer immunotherapy.

Optimizing the Spatial Density of Single Co Sites via Molecular Spacing for Facilitating Sustainable Water Oxidation.

Advances in single-atom (-site) catalysts (SACs) provide a new solution of atomic economy and accuracy for designing efficient electrocatalysts. In addition to a precise local coordination environment, controllable spatial active structure and tolerance under harsh operating conditions remain great challenges in the development of SACs. Here, we show a series of molecule-spaced SACs (msSACs) using different acid anhydrides to regulate the spatial density of discrete metal phthalocyanines with single Co sites, which significantly improve the effective active-site numbers and mass transfer, enabling one of the msSACs connected by pyromellitic dianhydride to exhibit an outstanding mass activity of (1.63 ± 0.01) × 105 A·g-1 and TOFbulk of 27.66 ± 1.59 s-1 at 1.58 V (vs RHE) and long-term durability at an ultrahigh current density of 2.0 A·cm-2 under industrial conditions for oxygen evolution reaction. This study demonstrates that the accessible spatial density of single atom sites can be another important parameter to enhance the overall performance of catalysts.

Temperature-Tuned Variable Confined Space for Modulating Dipolar Polarization of a Disc-Shaped Ammonium Ion.

Free accessible confined space and loose interaction are crucial for most solid-state ionic motions. Here, by using a near-spherical anion and a disc-shaped ammonium as two distinct but rigid building blocks, we report a new ionic crystal, (HMIm)3[La(NO3)6] (HMIm = 1-methyl-1H-imidazol-3-ium), in which the different confined spaces of three (HMIm)+ ions are fine-tuned over a broad temperature range. This effect can be utilized to modulate the dipolar polarization across a wide temperature/frequency range. Additionally, small-scale substitution of (HMIm)+ by its isomer of almost identical shape/size affords molecular solid solutions, which can further tune the dipolar polarization by varying the doping ratio. It is revealed that the differences in dipole moment and hydrogen bond rather than that of shape/size lead to a distorted crystalline environment for these solid solutions. Overall, we provide an exceptional model for understanding and regulating the dipole motion of polar aromatic molecules/ions in a crystalline environment.

Atomically Dispersed Dual-Metal Sites Showing Unique Reactivity and Dynamism for Electrocatalysis.

The real structure and in situ evolution of catalysts under working conditions are of paramount importance, especially for bifunctional electrocatalysis. Here, we report asymmetric structural evolution and dynamic hydrogen-bonding promotion mechanism of an atomically dispersed electrocatalyst. Pyrolysis of Co/Ni-doped MAF-4/ZIF-8 yielded nitrogen-doped porous carbons functionalized by atomically dispersed Co-Ni dual-metal sites with an unprecedented N8V4 structure, which can serve as an efficient bifunctional electrocatalyst for overall water splitting. More importantly, the electrocatalyst showed remarkable activation behavior due to the in situ oxidation of the carbon substrate to form C-OH groups. Density functional theory calculations suggested that the flexible C-OH groups can form reversible hydrogen bonds with the oxygen evolution reaction intermediates, giving a bridge between elementary reactions to break the conventional scaling relationship.

Biomass-Derived Carbon-Based Multicomponent Integration Catalysts for Electrochemical Water Splitting.

Electrocatalytic water splitting powered by sustainable electricity is a crucial approach for the development of new generation green hydrogen technology. Biomass materials are abundant and renewable, and the application of catalysis can increase the value of some biomass waste and turn waste into fortune. Converting economical and resource-rich biomass into carbon-based multicomponent integrated catalysts (MICs) has been considered as one of the most promising ways to obtain inexpensive, renewable and sustainable electrocatalysts in recent years. In this review, recent advances in biomass-derived carbon-based MICs towards electrocatalytic water splitting are summarized, and the existing issues and key aspects in the development of these electrocatalysts are also discussed and prospected. The application of biomass-derived carbon-based materials will bring some new opportunities in the fields of energy, environment, and catalysis, as well as promote the commercialization of new nanocatalysts in the near future.

A MnAl double adjuvant nanovaccine to induce strong humoral and cellular immune responses.

At present, the most widely used aluminum adjuvants have poor ability to induce effective Th1 type immune responses. Existing evidence suggests that manganese is a potential metal adjuvant by activating cyclic guanosine phospho-adenosine synthase (cGAS)-interferon gene stimulator protein (STING) signaling pathway to enhance humoral and cellular immune response. Hence, the effective modulation of metal components is expected to be a new strategy to improve the efficiency of vaccine immunization. Here, we constructed a manganese and aluminum dual-adjuvant antigen co-delivery system (MnO2-Al-OVA) to enhance the immune responses of subunit vaccines. Namely, the aluminum hydroxide was first fused on the surface of the pre-prepared MnO2 nanoparticles, which were synthesized by a simple redox reaction with potassium permanganate (KMnO4) and oleic acid (OA). The engineered MnO2-Al-OVA could remarkably promote cellular internalization and maturation of dendritic cells. After subcutaneous vaccination, MnO2-Al-OVA rapidly migrated into the lymph nodes (LNs) and efficiently activate the cGAS-STING pathway, greatly induced humoral and cellular immune responses. Of note, our findings underscore the importance of coordination manganese adjuvants in vaccine design by promoting the activation of the cGAS-STING-IFN-I pathway. With a good safety profile and facile preparation process, this dual-adjuvant antigen co-delivery nanovaccine has great potential for clinical translation prospects.

Cloaking Mesoporous Polydopamine with Bacterial Membrane Vesicles to Amplify Local and Systemic Antitumor Immunity.

As adjuvants or antigens, bacterial membranes have been widely used in recent antibacterial and antitumor research, but they are often injected multiple times to achieve therapeutic outcomes, with limitations in biosafety and clinical application. Herein, we leverage the biocompatibility and immune activation capacity of Salmonella strain VNP20009 to produce double-layered membrane vesicles (DMVs) for enhanced systemic safety and antitumor immunity. Considering the photothermal effect of polydopamine upon irradiation, VNP20009-derived DMVs are prepared to coat the surface of mesoporous polydopamine (MPD) nanoparticles, leading to the potential synergies between photothermal therapy mediated by MPD and immunotherapy magnified by DMVs. The single dose of MPD@DMV can passively target tumors and activate the immune system with upregulated T cell infiltration and secretion levels of pro-inflammatory factors as well as antitumor related cytokines. All of these promoted immune responses result in malignant melanoma tumor regression and extended survival time on local or distant tumor-bearing mouse models. Importantly, we further explore the advantages of intravenous injection of the MPD@DMV agent compared with its intratumoral injection, and the former demonstrates better long-term immune effects on animal bodies. Overall, this formulation design brings broader prospects for the autologous vaccine adjuvant by bacterial membrane vesicles in cancer therapy.

Self-Supporting Co/CeO2 Heterostructures for Ampere-Level Current Density Alkaline Water Electrolysis.

Remodeling the active surface through fabricating heterostructures can substantially enhance alkaline water electrolysis driven by renewable electrical energy. However, there are still great challenges in the synthesis of highly reactive and robust heterostructures to achieve both ampere-level current density hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Herein, we report a new Co/CeO2 heterojunction self-supported electrode for sustainable overall water splitting. The self-supporting Co/CeO2 heterostructures required only low overpotentials of 31.9 ± 2.2, 253.3 ± 2.7, and 316.7 ± 3 mV for HER and 214.1 ± 1.4, 362.3 ± 1.9, and 400.3 ± 3.7 mV for OER at 0.01, 0.5, and 1.0 A·cm-2, respectively, being one of the best Co-based bifunctional electrodes. Electrolyzer constructed from this electrode acting as an anode and cathode merely required cell voltages of 1.92 ± 0.02 V at 1.0 A·cm-2 for overall water splitting. Multiple characterization techniques combined with density functional theory calculations disclosed the different active sites on the anode and cathode, and the charge redistributions on the heterointerfaces that can optimize the adsorption of H and oxygen-containing intermediates, respectively. This study presents the tremendous prospective of self-supporting heterostructures for effective and economical overall water splitting.

Single-shot AAV-vectored vaccine against SARS-CoV-2 with fast and long-lasting immunity.

Due to the insufficient long-term protection and significant efficacy reduction to new variants of current COVID-19 vaccines, the epidemic prevention and control are still challenging. Here, we employ a capsid and antigen structure engineering (CASE) strategy to manufacture an adeno-associated viral serotype 6-based vaccine (S663V-RBD), which expresses trimeric receptor binding domain (RBD) of spike protein fused with a biological adjuvant RS09. Impressively, the engineered S663V-RBD could rapidly induce a satisfactory RBD-specific IgG titer within 2 weeks and maintain the titer for more than 4 months. Compared to the licensed BBIBP-CorV (Sinopharm, China), a single-dose S663V-RBD induced more endurable and robust immune responses in mice and elicited superior neutralizing antibodies against three typical SARS-CoV-2 pseudoviruses including wild type, C.37 (Lambda) and B.1.617.2 (Delta). More interestingly, the intramuscular injection of S663V-RBD could overcome pre-existing immunity against the capsid. Given its effectiveness, the CASE-based S663V-RBD may provide a new solution for the current and next pandemic.

Molecule-Enhanced Electrocatalysis of Sustainable Oxygen Evolution Using Organoselenium Functionalized Metal-Organic Nanosheets.

Remolding the reactivity of metal active sites is critical to facilitate renewable electricity-powered water electrolysis. Doping heteroatoms, such as Se, into a metal crystal lattice has been considered an effective approach, yet usually suffers from loss of functional heteroatoms during harsh electrocatalytic conditions, thus leading to the gradual inactivation of the catalysts. Here, we report a new heteroatom-containing molecule-enhanced strategy toward sustainable oxygen evolution improvement. An organoselenium ligand, bis(3,5-dimethyl-1H-pyrazol-4-yl)selenide containing robust C-Se-C covalent bonds equipped in the precatalyst of ultrathin metal-organic nanosheets Co-SeMON, is revealed to significantly enhance the catalytic mass activity of the cobalt site by 25 times, as well as extend the catalyst operation time in alkaline conditions by 1 or 2 orders of magnitude compared with these reported metal selenides. A combination of various in situ/ex situ spectroscopic techniques, ab initio molecular dynamics, and density functional theory calculations unveiled the organoselenium intensified mechanism, in which the nonclassical bonding of Se to O-containing intermediates endows adsorption-energy regulation beyond the conventional scaling relationship. Our results showcase the great potential of molecule-enhanced catalysts for highly efficient and economical water oxidation.

Triple functional mild photothermal improves gene editing of PD-L1 for enhanced antitumor immunity.

Traditional photothermal therapy ablates tumor cells by a high temperature (> 50 °C). Although it has shown good anti-tumor effect in animal models, the potential damages to healthy tissues and the unnecessary inflammatory reactions caused by the high temperature have hindered the clinical transitions of traditional photothermal therapy. In this study, we used polydopamine (PDA) as a mild photothermal material and control the maximum temperature below 45 °C, which not only avoided the side effects caused by a high temperature, but also ablated a fraction of tumor cells and produced tumor antigens. Meanwhile, the near-infrared (NIR) light also served as a "switch" to trigger the release of CRISPR/Cas9 RNP from Fe3O4 nanoparticles (Fe3O4 NPs) after their accumulation to tumor sites via magnetic targeting. The triple functional mild photothermal therapy achieved significant PD-L1 gene knockout efficiency in the tumor-bearing mice, reversed the condition of immunosuppression in the tumor microenvironment, led to a higher level of anti-tumor immune responses and effectively inhibited the growth of melanoma. We anticipate that this triple functional mild photothermal therapy would provide a potential new approach for the treatment of malignant tumors.

Highly selective generation of singlet oxygen from dioxygen with atomically dispersed catalysts.

Singlet oxygen (1O2) as an excited electronic state of O2 plays a significant role in ubiquitous oxidative processes from enzymatic oxidative metabolism to industrial catalytic oxidation. Generally, 1O2 can be produced through thermal reactions or the photosensitization process; however, highly selective generation of 1O2 from O2 without photosensitization has never been reported. Here, we find that single-atom catalysts (SACs) with atomically dispersed MN4 sites on hollow N-doped carbon (M1/HNC SACs, M = Fe, Co, Cu, Ni) can selectively activate O2 into 1O2 without photosensitization, of which the Fe1/HNC SAC shows an ultrahigh single-site kinetic value of 3.30 × 1010 min-1 mol-1, representing top-level catalytic activity among known catalysts. Theoretical calculations suggest that different charge transfer from MN4 sites to chemisorbed O2 leads to the spin-flip process and spin reduction of O2 with different degrees. The superior capacity for highly selective 1O2 generation enables the Fe1/HNC SAC as an efficient non-radiative therapeutic agent for in vivo inhibition of tumor cell proliferation.