Neutrophil-Mimetic, ROS Responsive, and Oxygen Generating Nanovesicles for Targeted Interventions of Refractory Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is the most prevalent inflammatory joint disease worldwide, leading to irreversible disability and even mortality. Unfortunately, current treatment regimens fail to cure RA due to low therapeutic responses and off-target side effects. Herein, a neutrophil membrane-cloaked, natural anti-arthritic agent leonurine (Leo), and catalase (CAT) co-loaded nanoliposomal system (Leo@CAT@NM-Lipo) is constructed to remodel the hostile microenvironment for RA remission. Due to the inflammation tropism inherited from neutrophils, Leo@CAT@NM-Lipo can target and accumulate in the inflamed joint cavity where high-level ROS can be catalyzed into oxygen by CAT to simultaneously accelerate the drug release and alleviate hypoxia at the lesion site. Besides, the neutrophil membrane camouflaging also enhances the anti-inflammatory potentials of Leo@CAT@NM-Lipo by robustly absorbing pro-arthritogenic cytokines and chemokines. Consequently, Leo@CAT@NM-Lipo successfully alleviated paw swelling, reduced arthritis score, mitigated bone and cartilage damage, and reversed multiple organ dysfunctions in adjuvant-induced arthritis rats (AIA) rats by synergistic effects of macrophage polarization, inflammation resolution, ROS scavenging, and hypoxia relief. Furthermore, Leo@CAT@NM-Lipo manifested excellent biocompatibility both at the cellular and animal levels. Taken together, the study provided a neutrophil-mimetic and ROS responsive nanoplatform for targeted RA therapy and represented a promising paradigm for the treatment of a variety of inflammation-dominated diseases.

Bioresponsive nanomedicines based on dynamic covalent bonds.

Trends in the development of modern medicine necessitate the efficient delivery of therapeutics to achieve the desired treatment outcomes through precise spatiotemporal accumulation of therapeutics at the disease site. Bioresponsive nanomedicine is a promising platform for this purpose. Dynamic covalent bonds (DCBs) have attracted much attention in studies of the fabrication of bioresponsive nanomedicines with an abundance of combinations of therapeutic modules and carrier function units. DCB-based nanomedicines could be designed to maintain biological friendly synthesis and site-specific release for optimal therapeutic effects, allowing the complex to retain an integrated structure before accumulating at the disease site, but disassembling into individual active components without compromising function in the targeted organs or tissues. In this review, we focus on responsive nanomedicines containing dynamic chemical bonds that can be cleaved by various specific stimuli, enabling achievement of targeted drug release for optimal therapy in various diseases.

Protein nanogels with enhanced pH-responsive dynamics triggered by remote NIR for systemic protein delivery and programmable controlled release.

Therapeutic proteins represent promising treatments in medical applications; however, direct administration of native proteins frequently suffers from in vivo enzymatic degradation or denaturation in hostile environments. Engineering proteins into biocompatible formulations can be used to solve these problems. Despite years of effort, efficient systemic delivery followed by successful release from the formulation remains a challenge. Herein, we describe a pH-responsive nanogel (PI825@PDC/protein NGs) formed by host-guest recognition of 6-arm PEGylated crystalline ß-cyclodextrin (ß-CD) and near-infrared IR825 dye, which affords highly efficient encapsulation of proteins during their self-assembly. PI825@PDC/protein NGs are robust enough to withstand hostile physiological conditions both in vitro and in vivo and could be slightly disassociated from protein release in acidic environments due to the anchored pH-responsive 2,3-dimethylmaleic anhydride (DMA) linker. Furthermore, the pH-responsive dynamics can be greatly enhanced by elevated temperature upon remote (Near-infrared spectroscopy) NIR irradiation of the IR825 within NGs, generating programmable release of loaded proteins for enhanced cancer treatment. This study describes a general method to load proteins with high efficiency for systemic delivery, followed by programmable protein release by remote NIR irradiation and offers new insights for protein engineering and potential medical applications.

pH-Sensitive Biomaterials for Drug Delivery.

The development of precise and personalized medicine requires novel formulation strategies to deliver the therapeutic payloads to the pathological tissues, producing enhanced therapeutic outcome and reduced side effects. As many diseased tissues are feathered with acidic characteristics microenvironment, pH-sensitive biomaterials for drug delivery present great promise for the purpose, which could protect the therapeutic payloads from metabolism and degradation during in vivo circulation and exhibit responsive release of the therapeutics triggered by the acidic pathological tissues, especially for cancer treatment. In the past decades, many methodologies, such as acidic cleavage linkage, have been applied for fabrication of pH-responsive materials for both in vitro and in vivo applications. In this review, we will summarize some pH-sensitive drug delivery system for medical application, mainly focusing on the pH-sensitive linkage bonds and pH-sensitive biomaterials.

Protein-drug conjugate programmed by pH-reversible linker for tumor hypoxia relief and enhanced cancer combination therapy.

Combining functional proteins with small molecular drugs into one entity may endow distinct synergistic advantages. However, on account of completely different physicochemical properties of such payloads, co-delivery through systemic administration for therapeutic purpose is challenging. Herein, we designed the protein-drug conjugate HSAP-DC-CAT (human serum albumin/Pt (IV)-dibenzocyclooctyne/chlorin e6-catalase) by modification of CAT and cisplatin pro-drug loaded HSA with pH-sensitive azide linker 3-(azidomethyl)-4-methyl-2,5-furandione (AzMMMan) followed by click chemistry assembly with DC. The dynamic covalent bonds between linker and proteins, on the one hand, can bridge proteins and small molecular drugs in the intermediate state for systemic delivery in the harsh in vivo environment; on the other hand, it can trigger traceless cleavage and release of drugs and proteins with full bioactivity in acidic microenvironment of tumor. The multifunctional HSAP-DC-CAT provides efficient cytosolic transduction in vitro, excellent blood half-lives after systemic administration, and significant antitumor outcome via integrated cisplatin-based chemotherapy and Ce6-based photodynamic therapy enhanced by catalase-induced manipulation of tumor hypoxia microenvironment. This study describes a universal formulation strategy for protein and small molecular drug by a bifunctional linker through amide reaction and click chemistry, with traceless in vivo release of therapeutic units.