Enhanced compound-protein binding affinity prediction by representing protein multimodal information via a coevolutionary strategy.

Due to the lack of a method to efficiently represent the multimodal information of a protein, including its structure and sequence information, predicting compound-protein binding affinity (CPA) still suffers from low accuracy when applying machine-learning methods. To overcome this limitation, in a novel end-to-end architecture (named FeatNN), we develop a coevolutionary strategy to jointly represent the structure and sequence features of proteins and ultimately optimize the mathematical models for predicting CPA. Furthermore, from the perspective of data-driven approach, we proposed a rational method that can utilize both high- and low-quality databases to optimize the accuracy and generalization ability of FeatNN in CPA prediction tasks. Notably, we visually interpret the feature interaction process between sequence and structure in the rationally designed architecture. As a result, FeatNN considerably outperforms the state-of-the-art (SOTA) baseline in virtual drug evaluation tasks, indicating the feasibility of this approach for practical use. FeatNN provides an outstanding method for higher CPA prediction accuracy and better generalization ability by efficiently representing multimodal information of proteins via a coevolutionary strategy.

Develop Targeted Protein Drug Carriers through a High-Throughput Screening Platform and Rational Design.

Protein-based drugs offer advantages, such as high specificity, low toxicity, and minimal side effects compared to small molecule drugs. However, delivery of proteins to target tissues or cells remains challenging due to the instability, diverse structures, charges, and molecular weights of proteins. Polymers have emerged as a leading choice for designing effective protein delivery systems, but identifying a suitable polymer for a given protein is complicated by the complexity of both proteins and polymers. To address this challenge, a fluorescence-based high-throughput screening platform called ProMatch to efficiently collect data on protein-polymer interactions, followed by in vivo and in vitro experiments with rational design is developed. Using this approach to streamline polymer selection for targeted protein delivery, candidate polymers from commercially available options are identified and a polyhexamethylene biguanide (PHMB)-based system for delivering proteins to white adipose tissue as a treatment for obesity is developed. A branched polyethylenimine (bPEI)-based system for neuron-specific protein delivery to stimulate optic nerve regeneration is also developed. The high-throughput screening methodology expedites identification of promising polymer candidates for tissue-specific protein delivery systems, thereby providing a platform to develop innovative protein-based therapeutics.

Controlled delivery of a neurotransmitter-agonist conjugate for functional recovery after severe spinal cord injury.

Despite considerable unmet medical needs, effective pharmacological treatments that promote functional recovery after spinal cord injury remain limited. Although multiple pathological events are implicated in spinal cord injuries, the development of a microinvasive pharmacological approach that simultaneously targets the different mechanisms involved in spinal cord injury remains a formidable challenge. Here we report the development of a microinvasive nanodrug delivery system that consists of amphiphilic copolymers responsive to reactive oxygen species and an encapsulated neurotransmitter-conjugated KCC2 agonist. Upon intravenous administration, the nanodrugs enter the injured spinal cord due to a disruption in the blood-spinal cord barrier and disassembly due to damage-triggered reactive oxygen species. The nanodrugs exhibit dual functions in the injured spinal cord: scavenging accumulated reactive oxygen species in the lesion, thereby protecting spared tissues, and facilitating the integration of spared circuits into the host spinal cord through targeted modulation of inhibitory neurons. This microinvasive treatment leads to notable functional recovery in rats with contusive spinal cord injury.

Porous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury.

The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered neuroinflammation. However, efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains a challenge. Here we present a device for the delivery of extracellular vesicles to treat spinal cord injury. We show that the device incorporating mesenchymal stem cells and porous microneedles enables the delivery of extracellular vesicles. We demonstrate that topical application to the spinal cord lesion beneath the spinal dura, does not damage the lesion. We evaluate the efficacy of our device in a contusive spinal cord injury model and find that it reduces the cavity and scar tissue formation, promotes angiogenesis, and improves survival of nearby tissues and axons. Importantly, the sustained delivery of extracellular vesicles for at least 7 days results in significant functional recovery. Thus, our device provides an efficient and sustained extracellular vesicles delivery platform for spinal cord injury treatment.

Correction: A biocompatible two-photon absorbing fluorescent mitochondrial probe for deep in vivo bioimaging.

Correction for 'A biocompatible two-photon absorbing fluorescent mitochondrial probe for deep in vivo bioimaging' by Lingmin Lin et al., J. Mater. Chem. B, 2022, DOI: 10.1039/d1tb02040d.

A biocompatible two-photon absorbing fluorescent mitochondrial probe for deep in vivo bioimaging.

Mitochondria, key organelles which keep in tune with energy demands for eukaryotic cells, are firmly associated with neurological conditions and post-traumatic rehabilitation. In vivo fluorescence imaging of mitochondria, especially with deep tissue penetration, would open a window to investigate the actual context of the brain. However, the depth of traditional two-photon mitochondrial fluorescence imaging is still limited due to the poor biological compatibility or low two-photon absorption cross-sections. A biocompatible mitochondria-targeted two-photon fluorescent dye (FO2) with an excellent two-photon absorption cross-section (the maximum of 1184 GM at 790 nm) and low cellular toxicity was designed and synthesized to overcome this problem. With this dye, we reached an imaging depth of ca. 640 µm during mitochondrial imaging of cortical cells in live animals. FO2 could be an excellent mitochondrial probe for live animal neural imaging to investigate the function and dysfunction of mitochondria in the brain.

Enzyme-Responsive Ag Nanoparticle Assemblies in Targeting Antibacterial against Methicillin-Resistant Staphylococcus Aureus.

The abuse of antibiotics resulted in the emergence of antibiotics-resistant bacteria, which has raised a great social concern together with the impetus to develop effective antibacterial materials. Herein, the synthesis of biocompatible enzyme-responsive Ag nanoparticle assemblies (ANAs) and their application in the high-efficiency targeted antimicrobial treatment of methicillin-resistant Staphylococcus aureus (MRSA) have been demonstrated. The ANAs could collapse and undergo stable/collapsed transition on approaching MRSA because of the serine protease-like B enzyme proteins (SplB)-triggered decomposition of the branched copolymers which have been employed as the macrotemplate in the synthesis of responsive ANAs. This transition contributed greatly to the high targeting affinity and efficiency of ANAs to MRSA. The minimum inhibitory concentration and minimum bactericidal concentration against MRSA were 2.0 and 32.0 µg mL-1, respectively. Skin wound healing experiments confirmed that the responsive ANAs could serve as an effective wound dressing to accelerate the healing of MRSA infection.

Unimolecular branched block copolymer nanoparticles in methanol for the preparation of poorly water-soluble drug nanoparticles.

Spherical unimolecular amphiphilic branched A-B block copolymer nanoparticles in methanol are fabricated via thermal annealing using the methanolic upper critical solution temperature (UCST) of the hydrophobic block segment. These polymer nanoparticles are then used to produce an aqueous poorly water-soluble drug nanoparticle suspension with a mass : drug ratio of 1 : 1 and 100% nanoparticle yield. The drug nanoparticles in the suspension are stabilized by multiple polymer nanoparticles.

Drug nanoparticles by emulsion-freeze-drying via the employment of branched block copolymer nanoparticles.

A large percentage of drug compounds exhibit low water solubility and hence low bioavailability and therapeutic efficacy. This may be addressed by preparation of drug nanoparticles, leading to enhanced dissolution rate and direct use for treatment. Various methods have been developed to produce drug nanocrystals, including wet milling, homogenization, solution precipitation, emulsion diffusion, and the recently developed emulsion freeze-drying. The drawback for these methods may include difficult control in particles size, use of surfactants & polymer, and low ratio of drug to stabilizer. Here, biocompatible branched block copolymer nanoparticles with lightly-crosslinked hydrophobic core and hydrophilic surface groups are synthesized by the direct monomer-to-particle methodology, characterized, and then used as scaffold polymer/surfactant to produce drug nanoparticles via the emulsion-freeze-drying approach. This method can be used for model organic dye and different poorly water-soluble drugs. Aqueous drug nanoparticle dispersions can be obtained with high ratio of drug to stabilizer and relatively uniform nanoparticle sizes.