In Vivo Polymer Mechanochemistry with Polynucleotides.

Polymer mechanochemistry utilizes mechanical force to activate latent functionalities in macromolecules and widely relies on ultrasonication techniques. Fundamental constraints of frequency and power intensity have prohibited the application of the polymer mechanochemistry principles in a biomedical context up to now, although medical ultrasound is a clinically established modality. Here, a universal polynucleotide framework is presented that allows the binding and release of therapeutic oligonucleotides, both DNA- and RNA-based, as cargo by biocompatible medical imaging ultrasound. It is shown that the high molar mass, colloidal assembly, and a distinct mechanochemical mechanism enable the force-induced release of cargo and subsequent activation of biological function in vitro and in vivo. Thereby, this work introduces a platform for the exploration of biological questions and therapeutics development steered by mechanical force.

Sonogenetics for Monitoring and Modulating Biomolecular Function by Ultrasound.

Ultrasound technology, synergistically harnessed with genetic engineering and chemistry concepts, has started to open the gateway to the remarkable realm of sonogenetics-a pioneering paradigm for remotely orchestrating cellular functions at the molecular level. This fusion not only enables precisely targeted imaging and therapeutic interventions, but also advances our comprehension of mechanobiology to unparalleled depths. Sonogenetic tools harness mechanical force within small tissue volumes while preserving the integrity of the surrounding physiological environment, reaching depths of up to tens of centimeters with high spatiotemporal precision. These capabilities circumvent the inherent physical limitations of alternative in vivo control methods such as optogenetics and magnetogenetics. In this review, we first discuss mechanosensitive ion channels, the most commonly utilized sonogenetic mediators, in both mammalian and non-mammalian systems. Subsequently, we provide a comprehensive overview of state-of-the-art sonogenetic approaches that leverage thermal or mechanical features of ultrasonic waves. Additionally, we explore strategies centered around the design of mechanochemically reactive macromolecular systems. Furthermore, we delve into the realm of ultrasound imaging of biomolecular function, encompassing the utilization of gas vesicles and acoustic reporter genes. Finally, we shed light on limitations and challenges of sonogenetics and present a perspective on the future of this promising technology.

Programming DNA Circuits for Controlled Immunostimulation through CpG Oligodeoxynucleotide Delivery.

Herein, we present a DNA circuit programmed for the delivery of CpG oligodeoxynucleotides (CpG ODNs) with the pharmacological immunostimulation function. The circuit employs a complementary DNA (cDNA) strand to deactivate the biological function of CpG ODNs via hybridization, while T7 exonuclease mediates the activation by hydrolyzing the cDNA and releasing the CpG ODN as an active moiety. We investigated the influence of several factors on the kinetic profile and temporal behavior of the circuit. These include the design of the cDNA strand, the concentration of the DNA duplex, and the concentration of T7 exonuclease. The DNA circuit's in vitro activation resulted in toll-like receptor 9 stimulation in the HEK-engineered cell line, as well as tumor necrosis factor-alpha release by J774A.1 macrophages. By programming the DNA circuit to control the release of the CpG ODN, we achieved an altered pharmacological profile with acute and potent immunostimulation, in comparison to a system without controlled CpG ODN release, which exhibited a slow and delayed response. Our findings demonstrate the potential of DNA circuits in controlling the pharmacological activity of DNA strands for controlled drug delivery.

Polymers Strive for Accuracy: From Sequence-Defined Polymers to mRNA Vaccines against COVID-19 and Polymers in Nucleic Acid Therapeutics.

Unquestionably, polymers have influenced the world over the past 100 years. They are now more crucial than ever since the COVID-19 pandemic outbreak. The pandemic paved the way for certain polymers to be in the spotlight, namely sequence-defined polymers such as messenger ribonucleic acid (mRNA), which was the first type of vaccine to be authorized in the U.S. and Europe to protect against the SARS-CoV-2 virus. This rise of mRNA will probably influence scientific research concerning nucleic acids in general and RNA therapeutics in specific. In this Perspective, we highlight the recent trends in sequence-controlled and sequence-defined polymers. Then we discuss mRNA vaccines as an example to illustrate the need of ultimate sequence control to achieve complex functions such as specific activation of the immune system. We briefly present how mRNA vaccines are produced, the importance of modified nucleotides, the characteristic features, and the advantages and challenges associated with this class of vaccines. Finally, we discuss the chances and opportunities for polymer chemistry to provide solutions and contribute to the future progress of RNA-based therapeutics. We highlight two particular roles of polymers in this context. One represents conjugation of polymers to nucleic acids to form biohybrids. The other is concerned with advanced polymer-based carrier systems for nucleic acids. We believe that polymers can help to address present problems of RNA-based therapeutic technologies and impact the field beyond the COVID-19 pandemic.

Reactive Oxygen Species: the Dual Role in Physiological and Pathological Conditions of the Human Body.

Reactive oxygen species (ROS) are well-known for playing a dual role as destructive and constructive species. Indeed, ROS are engaged in many redox-governing activities of the cells for the preservation of cellular homeostasis. However, its overproduction has been reported to result in oxidative stress, which is considered as a deleterious process, and is involved in the damage of cell structures that causes various diseased states. This review provides a concise view on some of the current research published in this topic for an improved understanding of the key roles of ROS in diverse conditions of health and disease. Previous research demonstrated that ROS perform as potential signaling molecules to control several normal physiological functions at the cellular level. Additionally, there is a growing body of evidence supporting the role of ROS in various pathological states. The binary nature of ROS with their profitable and injurious characteristics indicates the complexities of their specific roles at a biological compartment and the difficulties in establishing convenient intervention procedures to treat ROS-related diseases.

D-Serine in neurobiology: CNS neurotransmission and neuromodulation.

Homochirality is fundamental for life. L-Amino acids are exclusively used as substrates for the polymerization and formation of peptides and proteins in living systems. However, D- amino acids were recently detected in various living organisms, including mammals. Of these D-amino acids, D-serine has been most extensively studied. D-Serine was found to play an important role as a neurotransmitter in the human central nervous system (CNS) by binding to the N-methyl- D-aspartate receptor (NMDAr). D-Serine binds with high affinity to a co-agonist site at the NMDAr and, along with glutamate, mediates several vital physiological and pathological processes, including NMDAr transmission, synaptic plasticity and neurotoxicity. Therefore, a key role for D-serine as a determinant of NMDAr mediated neurotransmission in mammalian CNS has been suggested. In this context, we review the known functions of D-serine in human physiology, such as CNS development, and pathology, such as neuro-psychiatric and neurodegenerative diseases related to NMDAr dysfunction.