Development of a safe and effective carrier for systemic protein delivery is highly desirable, which depends on management of the relationship among loading capacity, stability, delivery efficiency, ...and degradability. Here, a tumor‐specific self‐degradable nanogel composed of hyaluronidase (HAase)‐degradable hyaluronic acid (HA) matrices entrapping acid‐activatable HAase (aHAase) for systemic delivery of anticancer proteins is reported. Collaboratively crosslinked nanogels (cNG) obtained by the synthetic cholesteryl methacrylated HA show high protein‐loading capacity and stability. The aHAase is engineered by modifying the HAase with citraconic anhydride to shield its HA‐degrading activity, which can be reversibly activated by hydrolysis of the citraconic amide under acidic condition. In the tumor microenvironment, the mild acidity activates the aHAase partially, which results in swelling of the cNG and releasing of the aHAase. The released reactivated aHAase can degrade the HA that is also a major constituent of tumor extracellular matrix to increase perfusion of the cNG in the tumor stroma. In the acidic endocytic vesicles, the aHAase is fully reactivated. The active aHAase completely degrades the cNG to release the encapsulated anticancer protein, deoxyribonuclease I intracellularly, which digests the DNA to cause tumor cell death for enhanced antitumor efficacy.
A collaboratively‐crosslinked hyaluronic acid‐based nanogel is developed with a high loading capacity for a variety of proteins and a favorable stability against plasma proteins. Equipped with acid‐activatable hyaluronidase, the nanogel possesses tumor‐acidity‐induced self‐degradability, which enables a programmable cascade delivery of anticancer protein for enhanced cancer therapy.
RNA‐based therapeutics is a promising approach for curing intractable diseases by manipulating various cellular functions. For eliciting RNA (i.e., mRNA and siRNA) functions successfully, the RNA in ...the extracellular space must be protected and it must be delivered to the cytoplasm. In this study, the development of a self‐degradable lipid‐like material that functions to accelerate the collapse of lipid nanoparticles (LNPs) and the release of RNA into cytoplasm is reported. The self‐degradability is based on a unique reaction “Hydrolysis accelerated by intra‐Particle Enrichment of Reactant (HyPER).” In this reaction, a disulfide bond and a phenyl ester are essential structural components: concentrated hydrophobic thiols that are produced by the cleavage of the disulfide bonds in the LNPs drive an intraparticle nucleophilic attack to the phenyl ester linker, which results in further degradation. An oleic acid‐scaffold lipid‐like material that mounts all of these units (ssPalmO‐Phe) shows superior transfection efficiency to nondegradable or conventional materials. The insertion of the aromatic ring is unexpectedly revealed to contribute to the enhancement of endosomal escape. Since the intracellular trafficking is a sequential process that includes cellular uptake, endosomal escape, the release of mRNA, and translation, the improvement in each process synergistically enhances the gene expression.
Cytoplasmic release of messenger RNA from its drug delivery system is one of the key steps that determines the efficiency of protein production. Intracellular collapse of lipid nanoparticles is facilitated by the self‐degradation of ionizable lipids via a unique intraparticle reaction denoted as “Hydrolysis accelerated by intra‐Particle Enrichment of Reactant (HyPER).”
A schematic representation of the tumor‐specific self‐degradable nanogels as potential carriers for systemic delivery of anticancer proteins described by Ran Mo and co‐workers in article number ...1707371. The cocoon as representation of the nanogel can protect the fragile protein during circulation and release the protein by self‐degradation under tumor acidic conditions, like the metamorphosis of a caterpillar to a butterfly.
Bionic functional coating plays a pivotal role in promoting internal fixation treatment of bone fracture. However, post-traumatic microenvironment characterized by hypoxia and acidic milieu, as well ...as high oxidative stress, may largely weaken the function of established coatings. Herein, we anchor two-dimensional H-silicene nanosheet (H-Si) onto hydroxyapatite (HA)-coated metal implant to develop a H-Si@HA composite coating. Benefiting from the intrinsic pH-responsive characteristics, the H-Si@HA maintains stable structure and functionalities in acidic milieu and simulates the superoxide dismutase and peroxidase-like activities, resulting in reactive oxygen species depletion, high oxidative stress suppression and further reversal of the acidic microenvironment. Meanwhile, H-Si@HA protects cells by inducing cellular autophagy. Sequentially, Si4+ release accompanying the degradation of the H-Si in neutral milieu promotes fracture healing by improving osteogenic-related gene expression of bone mesenchymal stem cells (BMSCs) and SOD1 expression of osteoprogenitor cells. Particularly, differentiated gene expression of BMSCs by the H-Si@HA coating was identified using absolute quantitative transcriptome sequencing, revealing that the H-Si could effectively modulate the expression of core mRNAs which are highly associated with osteogenesis and bone formation through regulating autophagy. Such a self-degradable nanoarmor coating illustrates the great clinic potential to achieve hierarchical and synergistic effect of fracture healing promotion.
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•The bionic coating demonstrates a hierarchical and synergistic effect of fracture healing promotion by H-Si intervention.•The unique pH-responsive feature enables excellent bone regeneration performance.•The underlying molecular mechanism of regulating differentiation of BMSCs induced by H-Si nanosheet is initially revealed.
In the pursuit of novel insecticides with high activity and a unique mode of action on the GABA receptor, a series of phenylpyrazole esterified derivatives (PEs) were synthesized using an improved ...Pinner reaction with high selectivity. Lewis acid catalysis was employed in a one-step solvent-thermal method to convert the cyano group of fipronil into an ester unit. FeCl3 was found to exhibit the highest selectivity for PEs synthesis, yielding PEs at 96.4%, with the byproduct being phenylpyrazole amide (PE 0 ) at 2.1%. Initial biological assays indicated superior insecticidal activity of the target compounds against Plutella xylostella and Mythimna separata compared to fipronil. Particularly, the smaller and shorter ester units, PE 3 , PE 5 , and PE 8 , demonstrated 2–2.5 times higher insecticidal activity against P. xylostella than fipronil. The higher activity of ester units compared to amide and acylhydrazone units can be attributed to the enhanced lipid solubility of PEs. Additionally, it may be due to the impact of PEs on the neurotransmitter nACh or the coordination of calcium and chloride ions with the ester’s −CO and −O– bonds, blocking the chloride ion channel. Hydrophobic parameters were confirmed by reversed-phase high-performance liquid chromatography (HPLC), indicating the enhanced lipophilicity conferred by the ester units of PEs. Molecular docking and CoMFA analysis preliminarily validated the strong interactions and structure–activity relationships between PEs and the GABA receptor and nACh receptor in P. xylostella. Furthermore, under simulated natural sunlight, PEs exhibited photodegradation capabilities, transforming back into fipronil parent fragments and enhancing their insecticidal activity. Moreover, PEs displayed excellent fluorescent properties, enabling self-detection of residues. These research findings provide new insights and directions for the development of efficient pesticides, with potential wide applications in the fields of medicine and biosensors.
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