RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration.

Chemically Modified Platforms for Better RNA Therapeutics.

Nature often uses dynamically assembling multienzymatic complexes called metabolons to achieve spatiotemporal control of complex metabolic reactions. Researchers are aiming to mimic this strategy of organizing enzymes to enhance the performance of artificial biocatalytic systems. Biomolecular condensates formed through liquid-liquid phase separation (LLPS) can serve as a powerful tool to drive controlled assembly of enzymes. Diverse enzymatic pathways have been reconstituted within catalytic condensates in vitro as well as synthetic membraneless organelles in living cells. Furthermore, in vivo condensates have been engineered to regulate metabolic pathways by selectively sequestering enzymes. Thus, harnessing LLPS for controlled organization of enzymes provides an opportunity to dynamically regulate biocatalytic processes. 

Phase-separated biomolecular condensates for biocatalysis.

Microbial cell factories (MCFs) convert low-cost carbon sources into valuable compounds. The CRISPR/Cas9 system has revolutionized MCF construction as a remarkable genome editing tool with unprecedented programmability. Recently, the CRISPR toolbox has been significantly expanded through the exploration of new CRISPR systems, the engineering of Cas effectors, and the incorporation of other effectors, enabling multi-level regulation and gene editing free of double-strand breaks. This expanded CRISPR toolbox powerfully promotes MCF construction by facilitating pathway construction, enzyme engineering, flux redistribution, and metabolic burden control. In this article, we summarize different CRISPR tool designs and their applications in MCF construction for gene editing, transcriptional regulation, and enzyme modulation. Finally, we also discuss future perspectives for the development and application of the CRISPR toolbox. 

The expanded CRISPR toolbox for constructing microbial cell factories.

Dynamic interactions of enzymes, including programmable configuration and cycling of enzymes, play important roles in the regulation of cellular metabolism. Here, we constructed a super DNA-enzymes molecule (SDEM) that comprises at least two cascade enzymes and multiple linked DNA strands to control and detect metabolism. We found that the programmable SDEM, which comprises glucose oxidase (GOx) and horseradish peroxidase (HRP), has a 20-fold lower detection limit and a 1.6-fold higher reaction rate than free enzymes. An SDEM can be assembled and disassembled using a hairpin structure and a displacement DNA strand to complete multiple cycles. An entropically driven catalytic assembly (catassembly) enables different SDEMs to switch from an SDEM with GOx and HRP cascades to an SDEM with sarcosine oxidase (SOX) and HRP cascades in over six orders of magnitude less time than without the catassembly to detect different metabolisms (GO and sarcosine) on demand. 

Programming Super DNA‐Enzyme Molecules for On‐Demand Enzyme Activity Modulation**

Abstract Plant respiration is a foundational biological process with the potential to be optimized to improve crop yield. To understand and manipulate the outputs of respiration, the inputs of respiration—respiratory substrates—need to be probed in detail. Mitochondria house substrate catabolic pathways and respiratory machinery, so transport into and out of these organelles plays an important role in committing substrates to respiration. The large number of mitochondrial carriers and catabolic pathways that remain unidentified hinder this process and lead to confusion about the identity of direct and indirect respiratory substrates in plants. The sources and usage of respiratory substrates vary and are increasing found to be highly regulated based on cellular processes and environmental factors. This review covers the use of direct respiratory substrates following transport through mitochondrial carriers and catabolism under normal and stressed conditions. We suggest the introduction of enzymes not currently found in plant mitochondria to enable serine and acetate to be direct respiratory substrates in plants. We also compare respiratory substrates by assessing energetic yields, availability in cells, and their full or partial oxidation during cell catabolism. This information can assist in decisions to use synthetic biology approaches to alter the range of respiratory substrates in plants. As a result, respiration could be optimized by introducing, improving, or controlling specific mitochondrial transporters and mitochondrial catabolic pathways.

/pdf/the-diversity-of-substrates-for-plant-respiration-and-how-to-qru98roq.pdf

The diversity of substrates for plant respiration and how to optimize their use

Dynamic modulation of enzyme activity by synthetic CRISPR–Cas6 endonucleases

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Dynamic modulation of enzyme activity by synthetic CRISPR–Cas6 endonucleases