Shulan Xiao

Transmembrane ionic flow through artificial ion channels is integral to the development of biohybrid electronics, such as neural interface technologies. However, achieving accurate and stable intracellular access through these synthetic analogues has remained a challenge. Here we use DNA origami tiles (0.8 nm diameter), anchored into live neuronal membranes, both with and without cholesterol tags, to demonstrate highly stable ion transport (net ~2 nS), channel-like stochasticity and intracellular drug delivery without disrupting neuronal physiology. These results are supported by molecular dynamics simulations. Using a suite of patch-clamp techniques, including two-photon-targeted variants, we obtain repeatable intracellular and quasi-intracellular voltage measurements across DNA tiles, eliminating the need for membrane break-in even from thin dendritic structures (~1 µm), which are inaccessible with standard electrodes. This advancement establishes an 'outside looking in' method to probe intracellular voltage dynamics using DNA nanostructure-based transmembrane access.

Biocompatible integration of synthetic materials with living tissue remains a major challenge for bioelectronics. In this case, substrate-free conducting polymer (CP) interfaces could help bridge this gap. We report in vivo assembly of n-doped poly(benzodifurandione) (n-PBDF) using whole blood–catalyzed polymerization in awake zebrafish and mice. This approach leverages endogenous catalysts, specifically hemoproteins, to form stable, thermally and ionically sensitive CP networks, ensuring long-term compatibility throughout the lifespan. We showcase the impact of this interface through reversible, cellular, and subcellular neuromodulation using near-infrared (NIR) light, including in vivo polymerized n-PBDF. Electrophysiological studies confirmed that n-PBDF alters intrinsic sodium ion channel excitability, and NIR light stimulation amplifies this modulation through thermoionic-induced shunting, providing on-demand, millisecond-scale reversible inhibitory control of excitability, a feature recapitulated in actively behaving mice.

Living systems process a broad range of internal and external stimuli, respond to environmental constraints, and adapt to various conditions through tight coordination between signaling networks and cellular mechanics. Among these, calcium signaling and cytoskeletal regulation form an essential interplay that spans multiple scales of biological organization—from ion–protein interactions to intercellular communication and tissue-level behaviors. Calcium ions (Ca2+) act as universal messengers, integrating a wide range of cellular signaling inputs to modulate a broad range of cellular structures and functions through the spatiotemporal dynamics of their concentration changes. Ca2+ signals follow conserved principles, despite their diverse roles, that define regulatory “Rules of Life” (RoLs)—generalized mechanisms that operate across biological contexts. This review focuses on how Ca2+ regulates and is regulated by cytoskeletal dynamics, with a particular emphasis on computational modeling for predictive simulations. As key examples, we highlight three specific RoLs: (1) Ca2+ dynamics facilitate cytoskeletal reorganization following stress and damage, (2) Ca2+ regulates actin dynamics to control synapse processes supporting both synapse formation and exocytosis, and (3) reciprocal coupling of spatiotemporal Ca2+ signaling and cellular dynamics defines distinct cellular roles in emergent multicellular behavior. Finally, we outline future directions toward developing multimodal computational simulations for identifying new RoLs, integrating them into multi-scale computational frameworks, and applications in bioengineering, pharmacology, and regenerative medicine.

Potassium channels control membrane potential and various physiological processes, including cell migration. However, the specific role of inwardly rectifying potassium channels in immune cell chemotaxis remains unknown. Here, we demonstrate that inwardly rectifying potassium channels, particularly Kir7.1 (Kcnj13), maintain the resting membrane potential and are crucial for directional sensing during neutrophil chemotaxis. Blocking or knocking out Kir in neutrophils disrupted their ability to sense direction toward different chemoattractants in multiple models. Using genetically encoded voltage indicators, we observed oscillating hyperpolarization during tail retraction in zebrafish neutrophils, with Kir7.1 required for depolarization toward the chemokine source. Focal depolarization via optogenetics biased pseudopod selection and triggered new protrusions, which depended on Gα signaling. Global hyperpolarization caused neutrophils to stall migration. Additionally, Kir influences GPCR signaling activation in dHL-60 cells. This research introduces membrane potential as a key component of the complex feedforward mechanism that links the adaptive and excitable networks necessary to guide immune cells in challenging tissue environments.