Toward the Integration of Machine Learning and Molecular Modeling for Designing Drug Delivery Nanocarriers.

The pioneering work on liposomes in the 1960s and subsequent research in controlled drug release systems significantly advances the development of nanocarriers (NCs) for drug delivery. This field is evolved to include a diverse array of nanocarriers such as liposomes, polymeric nanoparticles, dendrimers, and more, each tailored to specific therapeutic applications. Despite significant achievements, the clinical translation of nanocarriers is limited, primarily due to the low efficiency of drug delivery and an incomplete understanding of nanocarrier interactions with biological systems. Addressing these challenges requires interdisciplinary collaboration and a deep understanding of the nano-bio interface. To enhance nanocarrier design, scientists employ both physics-based and data-driven models. Physics-based models provide detailed insights into chemical reactions and interactions at atomic and molecular scales, while data-driven models leverage machine learning to analyze large datasets and uncover hidden mechanisms. The integration of these models presents challenges such as harmonizing different modeling approaches and ensuring model validation and generalization across biological systems. However, this integration is crucial for developing effective and targeted nanocarrier systems. By integrating these approaches with enhanced data infrastructure, explainable AI, computational advances, and machine learning potentials, researchers can develop innovative nanomedicine solutions, ultimately improving therapeutic outcomes.

A phosphatase-like nanomaterial promotes autophagy and reprograms macrophages for cancer immunotherapy.

Macrophages are plastic and play a key role in the maintenance of tissue homeostasis. In cancer progression, macrophages also take part in all processes, from initiation to progression, to final tumor metastasis. Although energy deprivation and autophagy are widely used for cancer therapy, most of these strategies do not target macrophages, resulting in undesired effects and unsatisfactory outcomes for cancer immunotherapy. Herein, we developed a lanthanum nickel oxide (LNO) nanozyme with phosphatase-like activity for ATP hydrolysis. Meanwhile, the autophagy of macrophages induced by LNO promotes the polarization of macrophages from M2-like macrophages (M2) to M1-like macrophages (M1) and reduces tumor-associated macrophages in tumor-bearing mice, exhibiting the capability of killing tumor-associated macrophages and antitumor effects in vivo. Furthermore, pre-coating the surface of LNO with a myeloid cell membrane significantly enhanced antitumor immunity. Our findings demonstrate that phosphatase-like nanozyme LNO can specifically induce macrophage autophagy, which improves therapeutic efficacy and offers valuable strategies for cancer immunotherapy.

Regulating Reactive Oxygen Intermediates of Fe-N-C SAzyme via Second-Shell Coordination for Selective Aerobic Oxidation Reactions.

Reactive oxygen species (ROS) regulation for single-atom nanozymes (SAzymes), e.g., Fe-N-C, is a key scientific issue that determines the activity, selectivity, and stability of aerobic reaction. However, the poor understanding of ROS formation mechanism on SAzymes greatly hampers their wider deployment. Herein, inspired by cytochromes P450 affording bound ROS intermediates in O2 activation, we report Fe-N-C containing the same FeN4 but with tunable second-shell coordination can effectively regulate ROS production pathways. Remarkably, compared to the control Fe-N-C sample, the second-shell sulfur functionalized Fe-N-C delivered a 2.4-fold increase of oxidase-like activity via the bound Fe=O intermediate. Conversely, free ROS (⋅O2 -) release was significantly reduced after functionalization, down to only 17 % of that observed for Fe-N-C. The detailed characterizations and theoretical calculations revealed that the second-shell sulfur functionalization significantly altered the electronic structure of FeN4 sites, leading to an increase of electron density at Fermi level. It enhanced the electron transfer from active sites to the key intermediate *OOH, thereby ultimately determining the type of ROS in aerobic oxidation process. The proposed Fe-N-Cs with different second-shell anion were further applied to three aerobic oxidation reactions with enhanced activity, selectivity, and stability.

pH-Activatable Pre-Nanozyme Mediated H2S Delivery for Endo-Exogenous Regulation of Oxidative Stress in Acute Kidney Injury.

Oxidative stress induced by excess reactive oxygen species (ROS) is a primary pathogenic cause of acute kidney injury (AKI). Development of an effective antioxidation system to mitigate oxidative stress for alleviating AKI remains to be investigated. This study presents the synthesis of an ultra-small Platinum (Pt) sulfur cluster (Pt5.65S), which functions as a pH-activatable prefabricated nanozyme (pre-nanozyme). This pre-nanozyme releases hydrogen sulfide (H2S) and transforms into a nanozyme (Ptzyme) that mimics various antioxidant enzymes, including superoxide dismutase and catalase, within the inflammatory microenvironment. Notably, the Pt5.65S pre-nanozyme exhibits an endo-exogenous synergy-enhanced antioxidant therapeutic mechanism. The Ptzyme reduces oxidative damage and inflammation, while the released H2S gas promotes proneurogenesis by activating Nrf2 and upregulating the expression of antioxidant molecules and enzymes. Consequently, the Pt5.65S pre-nanozyme shows cytoprotective effects against ROS/reactive nitrogen species (RNS)-mediated damage at remarkably low doses, significantly improving treatment efficacy in mouse models of kidney ischemia-reperfusion injury and cisplatin-induced AKI. Based on these findings, the H2S-generating pre-nanozyme may represent a promising therapeutic strategy for mitigating inflammatory diseases such as AKI and others.

Employing Noble Metal-Porphyrins to Engineer Robust and Highly Active Single-Atom Nanozymes for Targeted Catalytic Therapy in Nasopharyngeal Carcinoma.

Single-atom nanozymes (SANzymes) emerge as promising alternatives to conventional enzymes. However, chemical instability limits their application. Here, a systematic synthesis of highly active and stable SANzymes is presented by leveraging noble metal-porphyrins. Four noble metal-porphyrins are successfully synthesized to mimic the active site of natural peroxidases through atomic metal-N coordination anchored to the porphyrin center. These noble metal-porphyrins are integrated into a stable and biocompatible Zr-based metal-organic framework (MxP, x denoting Ir, Ru, Pt, and Pd). Among these, MIrP demonstrates superior peroxidase-like activity (685.61 U mg-1 ), catalytic efficiency, and selectivity compared to horseradish peroxidase (267.71 U mg-1 ). Mechanistic investigations unveil heightened catalytic activity of MIrP arises from its robust H2 O2 adsorption capacity, unique rate-determining step, and low energy threshold. Crucially, MIrP exhibits remarkable chemical stability under both room temperature and high H2 O2 concentrations. Further, through modification with (-)-Epigallocatechin-3-Gallate, a natural ligand for Epstein-Barr virus (EBV)-encoded latent membrane protein 1, targeted SANzyme (MIrPHE) tailored for EBV-associated nasopharyngeal carcinoma is engineered. This study not only presents an innovative strategy for augmenting the catalytic activity and chemical stability of SANzymes but also highlights the substantial potential of MIrP as a potent nanomedicine for targeted catalytic tumor therapy.

Reaction Mechanisms and Kinetics of Nanozymes: Insights from Theory and Computation.

"Nanozymes" usually refers to inorganic nanomaterials with enzyme-like catalytic activities. The research into nanozymes is one of the hot topics on the horizon of interdisciplinary science involving materials, chemistry, and biology. Although great progress has been made in the design, synthesis, characterization, and application of nanozymes, the study of the underlying microscopic mechanisms and kinetics is still not straightforward. Density functional theory (DFT) calculations compute the potential energy surfaces along the reaction coordinates for chemical reactions, which can give atomistic-level insights into the micro-mechanisms and kinetics for nanozymes. Therefore, DFT calculations have been playing an increasingly important role in exploring the mechanisms and kinetics for nanozymes in the past years. The calculations either predict the microscopic details for the catalytic processes to complement the experiments or further develop theoretical models to depict the physicochemical rules. In this review, the corresponding research progress is summarized. Particularly, the review focuses on the computational studies that closely interplay with the experiments. The relevant experimental results without DFT calculations will be also briefly discussed to offer a historic overview of how the computations promote the understanding of the microscopic mechanisms and kinetics of nanozymes.

Cascade nanozymatic network mimicking cells with selective and linear perception of H2O2.

A single stimulus leading to multiple responses is an essential function of many biological networks, which enable complex life activities. However, it is challenging to duplicate a similar chemical reaction network (CRN) using non-living chemicals, aiming at the disclosure of the origin of life. Herein, we report a nanozyme-based CRN with feedback and feedforward functions for the first time. It demonstrates multiple responses at different modes and intensities upon a single H2O2 stimulus. In the two-electron cascade oxidation of 3,3',5,5'-tetramethylbenzidine (TMB), the endogenous product H2O2 competitively inhibited substrates in the first one-electron oxidation reaction on a single-atom nanozyme (Co-N-CNTs) and strikingly accelerated the second one-electron oxidation reaction under a micellar nanozyme. As a proof-of-concept, we further confined the nanozymatic network to a microfluidic chip as a simplified artificial cell. It exhibited remarkable selectivity and linearity in the perception of H2O2 stimulus against more than 20 interferences in a wide range of concentrations (0.01-100 mM) and offered an instructive platform for studying primordial life-like processes.

Clear-Box Machine Learning for Virtual Screening of 2D Nanozymes to Target Tumor Hydrogen Peroxide.

Targeting tumor hydrogen peroxide (H2 O2 ) with catalytic materials has provided a novel chemotherapy strategy against solid tumors. Because numerous materials have been fabricated so far, there is an urgent need for an efficient in silico method, which can automatically screen out appropriate candidates from materials libraries for further therapeutic evaluation. In this work, adsorption-energy-based descriptors and criteria are developed for the catalase-like activities of materials surfaces. The result enables a comprehensive prediction of H2 O2 -targeted catalytic activities of materials by density functional theory (DFT) calculations. To expedite the prediction, machine learning models, which efficiently calculate the adsorption energies for 2D materials without DFT, are further developed. The finally obtained method takes advantage of both interpretability of physics model and high efficiency of machine learning. It provides an efficient approach for in silico screening of 2D materials toward tumor catalytic therapy, and it will greatly promote the development of catalytic nanomaterials for medical applications.

Spatial Well-defined Bimetallic Two-Dimensional Polymers with Single-Layer Thickness for Electrocatalytic Oxygen Evolution Reaction.

Innovative bimetallic materials provide more possibilities for further improving the performance of oxygen evolution reaction (OER) electrocatalysts. However, it is still a great challenge to rationally design bimetallic catalysts because there is not a practical way to decouple the factors influencing the intrinsic activity of active sites from others, thus hindering in-depth understanding of the mechanism. Herein, we provide a rational design of bimetallic Ni, Co two-dimensional polymer model OER catalyst. The well-defined architecture, identical density of active sites and monolayer characteristic allow us to decouple the intrinsic activity of active sites from other factors. The results confirmed that the relative position and local coordination environment has significant effect on the synergistic effect of the bimetallic centres. The highest electrocatalytic activity with the turnover frequency value up to 26.19 s-1 was achieved at the overpotential of 500 mV.

Metastable Iron Sulfides Gram-Dependently Counteract Resistant Gardnerella Vaginalis for Bacterial Vaginosis Treatment.

Bacterial vaginosis (BV) is the most common vaginal infection found in women in the world. Due to increasing drug-resistance of virulent pathogen such as Gardnerella vaginalis (G. vaginalis), more than half of BV patients suffer recurrence after antibotics treatment. Here, metastable iron sulfides (mFeS) act in a Gram-dependent manner to kill bacteria, with the ability to counteract resistant G. vaginalis for BV treatment. With screening of iron sulfide minerals, metastable Fe3 S4 shows suppressive effect on bacterial growth with an order: Gram-variable G. vaginalis >Gram-negative bacteria>> Gram-positive bacteria. Further studies on mechanism of action (MoA) discover that the polysulfide species released from Fe3 S4 selectively permeate bacteria with thin wall and subsequently interrupt energy metabolism by inhibiting glucokinase in glycolysis, and is further synergized by simultaneously released ferrous iron that induces bactericidal damage. Such multiple MoAs enable Fe3 S4 to counteract G. vaginalis strains with metronidazole-resistance and persisters in biofilm or intracellular vacuole, without developing new drug resistance and killing probiotic bacteria. The Fe3 S4 regimens successfully ameliorate BV with resistant G. vaginalis in mouse models and eliminate pathogens from patients suffering BV. Collectively, mFeS represent an antibacterial alternative with distinct MoA able to treat challenged BV and improve women health.

TiO2 supported single Ag atoms nanozyme for elimination of SARS-CoV2.

The outbreak of SARS-coronavirus 2 (SARS-CoV2) has become a global health emergency. Although enormous efforts have been made, there is still no effective treatment against the new virus. Herein, a TiO2 supported single-atom nanozyme containing atomically dispersed Ag atoms (Ag-TiO2 SAN) is designed to serve as a highly efficient antiviral nanomaterial. Compared with traditional nano-TiO2 and Ag, Ag-TiO2 SAN exhibits higher adsorption (99.65%) of SARS-CoV2 pseudovirus. This adsorption ability is due to the interaction between SAN and receptor binding domain (RBD) of spike 1 protein of SARS-CoV2. Theoretical calculation and experimental evidences indicate that the Ag atoms of SAN strongly bind to cysteine and asparagine, which are the most abundant amino acids on the surface of spike 1 RBD. After binding to the virus, the SAN/virus complex is typically phagocytosed by macrophages and colocalized with lysosomes. Interestingly, Ag-TiO2 SAN possesses high peroxidase-like activity responsible for reactive oxygen species production under acid conditions. The highly acidic microenvironment of lysosomes could favor oxygen reduction reaction process to eliminate the virus. With hACE2 transgenic mice, Ag-TiO2 SAN showed efficient anti-SARS-CoV2 pseudovirus activity. In conclusion, Ag-TiO2 SAN is a promising nanomaterial to achieve effective antiviral effects for SARS-CoV2.

A GGA + U investigation into the effects of cations on the electromagnetic properties of transition metal spinels.

Spinel oxides are promising low-cost catalysts with manifold and controllable physicochemical properties. Trial and error strategies cannot achieve the effective screening of high-performance spinel catalysts. Therefore, unraveling the structure-performance relationship is the foundation for their rational design. Herein, the effects of cations in tetrahedral and octahedral sites on the electronic structures of spinels were systematically investigated using GGA + U calculations based on ACr2O4 (A = Mn, Fe, Co, Ni, and Zn) and Zn/LiB2O4 (B = Cr, Mn, Fe, Co and Ni). The results indicate that the octahedrally coordinated B cations have notable influence on the electronic structures of spinels. The Jahn-Teller active ions Fe2+, Ni2+, Mn3+, Ni3+, Cr4+ and Fe4+ can remarkably reduce the band gaps of spinels and even change their electroconductibilities. These results will provide theoretical insights into the electronic properties of 3d transition metal spinels.

Origins of the peroxidase mimicking activities of graphene oxide from first principles.

Graphene-based nanomaterials, including graphene oxide (GO) and reduced graphene oxide (rGO), play key roles in the nanozyme field. GO and rGO carrying various oxygen-containing functional groups, including epoxy, hydroxyl, ether, endoperoxide, carbonyl, carboxyl, and ester, have been reported to display peroxidase mimicking activities. However, the active center and the underlying mechanism responsible for its peroxidase mimicking activities still remain unclear. Herein, taking the oxidation of 3,3,5,5-tetramethylbenzidine (TMB) by H2O2 as the model reaction, we investigate the possible catalytic mechanisms using DFT calculations. The results indicate that the carbonyl groups are the active centers. The activation of the C[double bond, length as m-dash]O bond is the key step in the catalytic cycle. The results will help realize the rational design of carbon-based nanozymes.

A biomimetic platelet based on assembling peptides initiates artificial coagulation.

Platelets play a critical role in the regulation of coagulation, one of the essential processes in life, attracting great attention. However, mimicking platelets for in vivo artificial coagulation is still a great challenge due to the complexity of the process. Here, we design platelet-like nanoparticles (pNPs) based on self-assembled peptides that initiate coagulation and form clots in blood vessels. The pNPs first bind specifically to a membrane glycoprotein (i.e., CD105) overexpressed on angiogenetic endothelial cells in the tumor site and simultaneously transform into activated platelet-like nanofibers (apNFs) through ligand-receptor interactions. Next, the apNFs expose more binding sites and recruit and activate additional pNPs, forming artificial clots in both phantom and animal models. The pNPs are proven to be safe in mice without systemic coagulation. The self-assembling peptides mimic platelets and achieve artificial coagulation in vivo, thus providing a promising therapeutic strategy for tumors.

eg occupancy as an effective descriptor for the catalytic activity of perovskite oxide-based peroxidase mimics.

A peroxidase catalyzes the oxidation of a substrate with a peroxide. The search for peroxidase-like and other enzyme-like nanomaterials (called nanozymes) mainly relies on trial-and-error strategies, due to the lack of predictive descriptors. To fill this gap, here we investigate the occupancy of eg orbitals as a possible descriptor for the peroxidase-like activity of transition metal oxide (including perovskite oxide) nanozymes. Both experimental measurements and density functional theory calculations reveal a volcano relationship between the eg occupancy and nanozymes' activity, with the highest peroxidase-like activities corresponding to eg occupancies of ~1.2. LaNiO3-δ, optimized based on the eg occupancy, exhibits an activity one to two orders of magnitude higher than that of other representative peroxidase-like nanozymes. This study shows that the eg occupancy is a predictive descriptor to guide the design of peroxidase-like nanozymes; in addition, it provides detailed insight into the catalytic mechanism of peroxidase-like nanozymes.

Dioxygen activation with stable N-heterocyclic carbenes.

Dioxygen activation with both cyclic (amino)(alkyl)carbenes and di(amino)carbenes at ambient temperature is described. Theoretical studies suggest that electron rearrangement from the doubly filled σ orbital of carbene carbon to its vacant p orbital through the π* antibonding orbital of 3O2 can be considered for Ccarbene-O bond formation.

Methanol-Assisted Phthalimide Ring Opening: Concerted or Stepwise Mechanism?

The opening of the five-membered ring is the essential step for phthalimide and its derivatives to be used as the reactants in many chemical synthetic routes. Reportedly, such ring opening follows the concerted mechanism in methanol solvent, which, however, has an unreasonably high energy barrier (36.3 kcal mol-1 at the M06-2X/6-311++G(d,p) level of theory). By density functional theory calculations, we report that this ring opening prefers the alternatively stepwise mechanism. The stepwise mechanism has a much lower energy barrier (21.0 kcal mol-1 at the same level of theory) and thus is much more completive than the concerted one. The stepwise mechanism should be considered as the dominant mechanism responsible for the phthalimide ring opening when studying the kinetics of the relevant synthetic reactions in the future.

Computational Study on the Mechanisms of Multiple Complexation of CO and Isonitrile Ligands to Boron.

The recent experimental realization of compound Tripp-B(CO)2 (denoted as 2a), where Tripp is 2,6-di(2,4,6-triisopropylphenyl)-phenyl), breaks through conventional knowledge that only transition metals can bind more than one CO to form multicarbonyl adducts. Compound 2a is stable in air but liberates CO under light. The B-CO bonds of 2a are considered to be similar to donor-acceptor bonds of transition metal complexes. To address the formation mechanism and chemical bonding of this novel type of boron compounds, we present a density functional theory study on the formation and photolysis of 2a and similar compounds. The results suggest that the formation of 2a is facile by three consecutive additions of CO to the terminal borylene metal complex, that is, the boron source of the synthesis. These CO additions can be practically accomplished via two different paths: CO direct addition and CO migration followed by addition. Such mechanisms can be excellently rationalized by the donor-acceptor bonding model of the terminal borylene complex, which in turn suggests that using donor-acceptor bonds for 2a is natural for understanding the mechanisms. Liberation of CO from 2a and its similar compounds has higher energy barriers at the ground states than that at the triplet states by 40 kcal/mol. These energy barriers explain the experimentally observed air stability and photolysis of these compounds. The results for the first time provide mechanistic insights for the unprecedented chemical processes; they allow evaluation of the applicability of donor-acceptor bonding in main-group compounds from the new perspective of chemical reactions.

Metal-like Boronic-Organic Frameworks: A Design and Computation.

Because of the lack of strong π-interaction in their bonds connecting building units, most of the metal-organic frameworks (MOFs) and covalent-organic frameworks (COFs) achieved so far are insulators or wide-bandgap semiconductors. The design of metal-like frameworks based on known chemical components is a challenge. This work reports that aryl borons can be linked together through isocyanides to form stable and easily accessible low-dimensional boronic-organic frameworks (BOFs). Particularly, the boron atoms in the BOFs behave like transition metals, forming the combined σ-donation and π-backdonation bonds instead of the usual electron-sharing bonds with the isocyanide linkers. This peculiar bonding endows BOFs with semimetal and narrow-bandgap semiconductor features, which are different from MOFs and COFs and may be found to be useful in future nanoelectronics. The results open a door to integrating the knowledge of the donor-acceptor chemistry in the main group into materials science.