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Abstract Efficient delivery of biomolecules into neurons has significant impacts on therapeutic applications in the central nervous system (CNS) and fundamental neuroscience research. Existing viral and non‐viral delivery methods often suffer from inefficient intracellular access due to the endocytic pathway. Here, a neuron‐targeting and direct cytosolic delivery platform is discovered by using a 15‐amino‐acid peptide, termed the N1 peptide, which enables neuron‐specific targeting and cytosolic delivery of functional biomolecules. The N1 peptide initially binds hyaluronan in the extracellular matrix and subsequently passes the membrane of neurons without being trapped into endosome. This mechanism facilitates the efficient delivery of cell‐impermeable and photo‐stable fluorescent dye for super‐resolution imaging of dendritic spines, and functional proteins, such as Cre recombinase, for site‐specific genome modification. Importantly, the N1 peptide exhibits robust neuronal specificity across diverse species, including mice, rats, tree shrews, and zebra finches. Its targeting capability is further demonstrated through various administration routes, including intraparenchymal, intrathecal, and intravenous (i.v.) injections after blood‐brain barrier (BBB) opening with focused ultrasound (FUS). These findings establish the N1 peptide as a versatile and functional platform with significant potential for bioimaging and advanced therapeutic applications. 

Abstract Optical tweezers have profound importance across fields ranging from manufacturing to biotechnology. However, the requirement of refractive index contrast and high laser power results in potential photon and thermal damage to the trapped objects, such as nanoparticles and biological cells. Optothermal tweezers have been developed to trap particles and biological cells via opto-thermophoresis with much lower laser powers. However, the intense laser heating and stringent requirement of the solution environment prevent their use for general biological applications. Here, we propose hypothermal opto-thermophoretic tweezers (HOTTs) to achieve low-power trapping of diverse colloids and biological cells in their native fluids. HOTTs exploit an environmental cooling strategy to simultaneously enhance the thermophoretic trapping force at sub-ambient temperatures and suppress the thermal damage to target objects. We further apply HOTTs to demonstrate the three-dimensional manipulation of functional plasmonic vesicles for controlled cargo delivery. With their noninvasiveness and versatile capabilities, HOTTs present a promising tool for fundamental studies and practical applications in materials science and biotechnology. 

Abstract Live imaging of the brain extracellular matrix (ECM) provides vital insights into changes that occur in neurological disorders. Current techniques such as second or third‐harmonic generation offer limited contrast for live imaging of the brain ECM. Here, a new method, pan‐ECM via chemical labeling of extracellular proteins, is introduced for live brain ECM imaging. pan‐ECM labels all major ECM components in live tissue including the interstitial matrix, basement membrane, and perineuronal nets. pan‐ECM enables in vivo observation of the ECM heterogeneity between the glioma core and margin, as well as the assessment of ECM deterioration under stroke condition, without ECM shrinkage from tissue fixation. These findings indicate that the pan‐ECM approach is a novel way to image the entire brain ECM in live brain tissue with optical resolution. pan‐ECM has the potential to advance the understanding of ECM in brain function and neurological diseases. 

A phenol molecule is shown at its free energy minimum in atransazo-PC lipid bilayer, where it interacts with the azobenzene groups that are incorporated into one of the two phosphatidylcholine lipid tails. 

The human brain represents one of the most complex biological systems, containing billions of neurons interconnected through trillions of synapses. Inherent to the brain is a biochemical complexity involving ions, signaling molecules, and peptides that regulate neuronal activity and allow for short- and long-term adaptations. Large-scale and noninvasive imaging techniques, such as fMRI and EEG, have highlighted brain regions involved in specific functions and visualized connections between different brain areas. A major shortcoming, however, is the need for more information on specific cell types and neurotransmitters involved, as well as poor spatial and temporal resolution. Recent technologies have been advanced for neuronal circuit mapping and implemented in behaving model organisms to address this. Here, we highlight strategies for targeting specific neuronal subtypes, identifying, and releasing signaling molecules, controlling gene expression, and monitoring neuronal circuits in real-timein vivo. Combined, these approaches allow us to establish direct causal links from genes and molecules to the systems level and ultimately to cognitive processes.