Bioorthogonal cleavage chemistry has been rapidly emerging as a powerful tool for manipulation and gain-of-function studies of biomolecules in living systems. While the initial bond formation-centered bioorthogonal reactions have been widely adopted for labeling, tracing, and capturing biomolecules, the newly developed bond cleavage-enabled bioorthogonal reactions have opened new possibilities for rescuing small molecules as well as biomacromolecules in living systems, allowing multidimensional controls over biological processes in vitro and in vivo. In this Outlook, we first summarized the development and applications of bioorthogonal cleavage reactions (BCRs) that restore the functions of chemical structures as well as more complex networks, including the liberation of prodrugs, release of bioconjugates, and in situ reactivation of intracellular proteins. As we embarked on this fruitful progress, we outlined the unmet scientific needs and future directions along this exciting avenue. We believe that the potential of BCRs will be further unleashed when combined with other frontier technologies, such as genetic code expansion and proximity-enabled chemical labeling.

Unleashing the Power of Bond Cleavage Chemistry in Living Systems

Hierarchical self-assembly (HAS) is a powerful approach to create supramolecular nanostructures for biomedical applications. This potency, however, is generally challenged by the difficulty of controlling the HAS of biomacromolecules and the functionality of resulted HAS nanostructures. Herein, we report a modular approach for controlling the HAS of discrete metal-organic cages (MOC) into supramolecular nanoparticles, and its potential for intracellular protein delivery and cell-fate specification. The hierarchical coordination-driven self-assembly of adamantane-functionalized M12 L24 MOC (Ada-MOC) and the host-guest interaction of Ada-MOC with β-cyclodextrin-conjugated polyethylenimine (PEI-βCD) afford supramolecular nanoparticles in a controllable manner. HAS maintains high efficiency and orthogonality in the presence of protein, enabling the encapsulation of protein into the nanoparticles for intracellular protein delivery for therapeutic application and CRISPR/Cas9 genome editing.

Hierarchical Self-assembly of Discrete Metal-Organic Cages into Supramolecular Nanoparticles for Intracellular Protein Delivery.

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes. Through metabolic engineering, bioorthogonal groups can be tagged onto cell membranes, which selectively attach to cargos with paired groups via bioorthogonal reactions. Due to its simplicity, high efficiency, and specificity, bioorthogonal chemistry has demonstrated great application potential in drug delivery. On the one hand, bioorthogonal reactions improve therapeutic agent delivery to target sites, overcoming off-target distribution. On the other hand, nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions, providing approaches to developing multi-functional drug delivery systems (DDSs). In this review, we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups. We then highlight recent breakthroughs in developing active targeting DDSs to tumors, immune systems, or bacteria by bioorthogonal chemistry, as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs (biomimetic DDSs, cell-based DDSs, bacteria-based and phage-based DDSs) and hydrogels. Finally, we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery. We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment. 

/pdf/recent-advances-in-developing-active-targeting-and-multi-3ixzqwg6.pdf

Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

Simple Summary Chemotherapy has been widely used in clinic to treat various types of tumors, although severe side effects have been the most critical limitation of this treatment modality. For a long time, it has been believed that toxicity derives from the apoptosis of normal cells induced by the use of chemotherapeutic drugs due to their off-target biodistribution. In 2017, a breakthrough finding by Shao Feng’s group showed that the side effects were related to pyroptosis caused by chemotherapeutic-drug-induced GSDME activation, and, interestingly, pyroptosis shares the same upstream signaling molecule with apoptosis, i.e., the caspase-3 activation. From then on, great research attention has been paid to chemotherapy-induced pyroptosis. In reality, pyroptosis is a “double-edged sword”, causing side effects in normal tissue, but also being able to promote antitumor effects, owing to its regulation of antitumor immunity. Therefore, rationally balancing the cell apoptosis and pyroptosis of caspase-3-activating chemotherapy is critically important for better antitumor therapy. This critical review aims to summarize recent progress in the field, focusing on how to balance cell apoptosis and pyroptosis for better tumor chemotherapy. Abstract Chemotherapy is a standard treatment modality in clinic that exerts an antitumor effect via the activation of the caspase-3 pathway, inducing cell death. While a number of chemotherapeutic drugs have been developed to combat various types of tumors, severe side effects have been their common limitation, due to the nonspecific drug biodistribution, bringing significant pain to cancer patients. Recently, scientists found that, besides apoptosis, chemotherapy could also cause cell pyroptosis, both of which have great influence on the therapeutic index. For example, cell apoptosis is, generally, regarded as the main mechanism of killing tumor cells, while cell pyroptosis in tumors promotes treatment efficacy, but in normal tissue results in toxicity. Therefore, significant research efforts have been paid to exploring the rational modulation mode of cell death induced by chemotherapy. This critical review aims to summarize recent progress in the field, focusing on how to balance cell apoptosis and pyroptosis for better tumor chemotherapy. We first reviewed the mechanisms of chemotherapy-induced cell apoptosis and pyroptosis, in which the activated caspase-3 is the key signaling molecule for regulating both types of cell deaths. Then, we systematically discussed the rationale and methods of switching apoptosis to pyroptosis for enhanced antitumor efficacy, as well as the blockage of pyroptosis to decrease side effects. To balance cell pyroptosis in tumor and normal tissues, the level of GSDME expression and tumor-targeting drug delivery are two important factors. Finally, we proposed potential future research directions, which may provide guidance for researchers in the field.

/pdf/balance-cell-apoptosis-and-pyroptosis-of-caspase-3-302q75wu.pdf

Balance Cell Apoptosis and Pyroptosis of Caspase-3-Activating Chemotherapy for Better Antitumor Therapy

Hydrogen-bonded organic framework-based bioorthogonal catalysis prevents drug metabolic inactivation

The abundance of bacterial effectors have inspired us to explore their potential in rewiring malignant cell signaling. Their incapability for entering cells, however, hinders such application. Herein we developed a cationic lipid-based high throughput library screening platform for effective intracellular delivery of bacterial effectors. As the misregulated MAPK signaling is a hallmark of many types of cancer, we turned to the Shigella effector OspF which irreversibly inactivates ERK, the terminal component of MAPK cascade. We created a function-based screening assay to obtain AMPA-O16B lipid nanoparticles for effective OspF intracellular delivery, which inhibited the malignant MAPK signaling and tumor growth in vitro and in vivo. Furthermore, the optimized lipid nanoparticle formulation can deliver OspF to modulate the immunosuppressive responses in macrophages. Our work is a general strategy to explore the therapeutic potentials of naturally evolved bacterial effectors.

Cationic Lipid-based Intracellular Delivery of Bacterial Effectors for Rewiring Malignant Cell Signaling.

The complicated and entangled cell signaling network is dynamically regulated by a wide array of enzymes such as kinases. It remains desirable but challenging to specifically modulate individual, endogenous kinases within a cell, particularly in a spatial–temporally controlled fashion. Current strategies toward regulating the intracellular functions of a kinase of interest either lack specificity or require genetic engineering that may perturb its physiological activity. Herein, we harnessed a bacterial effector OspF for optical and chemical modulation of the endogenous mitogen-activated protein kinase (MAPK) cascade in living cells and mice. The phospho-lyase OspF provided high specificity and spatial resolution toward the desired kinase such as the extracellular signal-regulated kinase (ERK), while the genetically encoded bioorthogonal decaging strategy enabled its temporal activation in living systems. The photocaged OspF (OspF*) was applied to dissect the subcellular signaling roles of ERK in nucleus ...

Bioorthogonal Engineering of Bacterial Effectors for Spatial-Temporal Modulation of Cell Signaling.

Conventional protein engineering methods for modifying protein nanopore are typically limited to 20 natural amino acids, which restricts the diversity of nanopore in structure and function. To enrich the chemical environment inside the nanopore, we employed the genetic code expansion (GCE) technique to site-specifically incorporate unnatural amino acid (UAA) into the sensing region of aerolysin nanopore. This approach leveraged the efficient pyrrolysine-based aminoacyl-tRNA synthetase-tRNA pair for a high yield of pore-forming protein. Both molecular dynamics (MD) simulations and single-molecule sensing experiments demonstrated that the conformation of UAA residues provided a favorable geometric orientation for the interactions of target molecules and the pore. This reasonably designed chemical environment enabled the direct discrimination of multiple peptides containing hydrophobic amino acids. Our work provides a new framework to endow unique sensing properties to nanopore that are difficult to achieve using classical protein engineering approaches.

Controlled Genetic Encoding of Unnatural Amino Acid in Protein Nanopore.

Pyroptosis is an inflammatory cell death form triggered by protease-mediated truncation and release of the N-terminal pore-forming domain of the gasdermin (GSDM) family proteins in various cell types. We report a Bioorthogonally ACtivatable Base editor (BaseBAC) for in situ and on-demand initiation of cell-type-specific pyroptosis. We first made the enzymatic activity of a cytosine base editor (CBE) switchable by establishing a bioorthogonal blockage on the PAM-interacting residue to control its DNA-binding ability. The resulting BaseBAC allowed in situ control of base editing on the GSDME gene that switched to the truncated expression of its N-terminal domain to activate pyroptosis. BaseBAC offers a general method for on-demand awakening of functional domains of self-inhibiting proteins and the corresponding cellular processes with high specificity in living systems.

Bioorthogonally Activatable Base Editing for On-Demand Pyroptosis.

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Papers

Cationic Lipid-based Intracellular Delivery of Bacterial Effectors for Rewiring Malignant Cell Signaling.

Bioorthogonal Engineering of Bacterial Effectors for Spatial-Temporal Modulation of Cell Signaling.

Controlled Genetic Encoding of Unnatural Amino Acid in Protein Nanopore.

Bioorthogonally Activatable Base Editing for On-Demand Pyroptosis.