Conspectus The further development of lipid nanocarriers remains central to advancing next-generation nanomedicine and gene delivery. Although clinically approved lipid nanoparticles (LNPs) have achieved remarkable clinical impact, especially during the COVID-19 pandemic, their reliance on endocytosis often leads to endosomal degradation and low cytosolic delivery efficiency; e.g., typically less than 10% of mRNA in the clinical COVID-19 vaccines reaches the cytosol. Lyotropic liquid crystalline LNPs with internal inverse cubic phases, namely, cubosomes, present an attractive alternative owing to their intrinsic fusogenicity with biological membranes. Their lipid bilayer architecture promotes fusion with plasma or endosomal membranes, providing a pathway for efficient cytosolic release of therapeutic cargo. The fusion behavior of individual cubosomes remained elusive for many years due to limitations in sufficient spatiotemporal resolution and the complexity of disentangling multiple interactions occurring simultaneously. Another major barrier to exploiting cubosomes in nanomedicine has been the lack of control over particle size in the traditional homogenization preparation method, restricting both fundamental research and large-scale industrial translation. For nano–bio interactions, the connections between the LNP properties, including internal nanostructure and particle size, with their biological performance are still poorly defined. For more than two decades, our Molecular Assembly Lab has had extensive experience with amphiphile self-assembly, particularly in the preparation, characterization, and application of cubosomes. In this Account, we focus on introducing our progress on cubosomes since 2019, including the mechanistic understanding of their membrane fusion behavior, microfluidic-based formation with precise size control, phase- and size-dependent nano–bio interactions across multiple in vitro mammalian cells and bacteria systems, and proof-of-concept therapeutic applications. We have deciphered that the fusion behavior of lipid dye-labeled cubosomes with supported lipid bilayers (SLBs), mammalian cell membranes, and the outer membrane of Gram-negative bacteria follows a universal scaling law of lipid dye fluorescence intensity over time, I ∼ t–1/6, as characterized by advanced total internal reflection fluorescence microscopy (TIRF). Moreover, we have tailored cubosome sizes with precise control from 130 nm to over 300 nm using a commercial microfluidic platform following a quantitative scaling law with total flow rate (Q), Size ∼ Q–0.15. A systematic in vitro evaluation of how the mesophase and particle size of LNPs modulate biological performance revealed that lipid nanocarriers with cubic phases and smaller sizes displayed stronger cell association, compared to their corresponding counterparts. Finally, we demonstrated enhanced antibiotic penetration across bacterial envelopes and elevated antimicrobial efficiency via fusion-mediated transport when antimicrobials were carried by cubosomes as a proof-of-concept. We have also highlighted the therapeutic potential of cubosomes for the delivery of diverse cargos, such as anticancer drugs, thrombolytic agents, and nucleic acids, expanding the clinical impact to broader nanomedicine frontiers.
Conspectus Precise treatment of intractable diseases such as cancer using nanomachines epitomizes a grand aspiration in biomedical science. Among the various approaches, nanomachines offer a promising route with molecular precision. Despite notable progress in recent decades, clinical translation of such machines remains constrained by the complexity of the physiological environment. Multitiered biological barriers limit their targeted distribution across human-scale distances, while intricate bionano interactions raise substantial challenges concerning in vivo efficacy, targeting specificity, and biocompatibility. DNA, the primary carrier of genetic information, is now repurposed to exhibit functions that extend beyond the central dogma. Leveraging its programmable and predictable self-assembly, DNA has become a transformative material for engineering precise nanoscale structures, molecular circuits, and functional nanomachines, demonstrating increasing translational potential in biomedicine. In this Account, we review recent advances in the design of DNA framework nanomachines. We first introduce programmable DNA frameworks, which serve as versatile platforms for the precise, nanoscale spatial organization of functional modules, resulting in emergent properties and functionalities differing from conventional DNA molecules. We next describe how DNA structures generate mechanical outputs, such as structural reconfiguration, establishing the foundation for nanomachines. Meanwhile, DNA computation, driven by molecular reactions, has demonstrated capabilities including Boolean logic, pattern recognition, and temporally resolved discrimination of multiple inputs. We discuss the integration of mechanical actuation and DNA computation into intelligent nanomachines, which can sense environmental cues, process complex environmental information and produce structural-functional outputs. Importantly, these structures can be engineered to traverse in vivo hierarchical biological barriers, from tissues and cells to subcellular compartments. We discuss how DNA framework structures overcome like-charge attraction with cell membranes via corner-attack modes and caveolin-mediated uptake, penetrate skin and ocular barriers in a size-dependent manner, and achieve renal or lymphatic targeting. Recent investigations have elucidated critical interactions between these nanostructures and multilevel biological interfaces, such as immune modulatory effects, thereby illuminating their underlying mechanisms and advancing clinical translation prospects. We propose that topical drug delivery based on DNA frameworks is approaching clinical translation. In the near term, plausible directions include systemic delivery applications such as kidney disease diagnosis and treatment, as well as vaccination against pathogens and tumors. Looking ahead, intelligent DNA framework nanomachines may implement automated, adaptive, multidimensional theranostics, advancing the vision of precision medicine. We discuss several persistent challenges, including structural and functional instability in vivo, potential biosafety concerns, and substantial gaps between animal models and human patients. We also outline possible solutions, such as AI-assisted design, microfluidics-based manufacturing, and humanized models.
Conspectus Leveraging the predictability of Watson–Crick base pairing and the programmability of nucleic-acid structures, DNA nanodevices can be rationally designed into diverse architectures that incorporate functional motifs such as aptamers and DNAzymes. These multifunctional constructs enable the integration of target recognition, signal transduction, and amplification within a single framework, facilitating versatile biomolecular sensing. However, translating conventional DNA nanodevices into practical applications within complex biological samples remains challenging due to their high susceptibility to nuclease degradation, which compromises structural integrity and leads to signal leakage. Additionally, the low abundance of target analytes and the crowded nature of biological fluids significantly reduce molecular collision frequency and slow interfacial reaction kinetics, thereby resulting in poor sensitivity and a high detection limit. Therefore, developing next-generation DNA nanodevices with enhanced structural stability and improved reaction efficiency is crucial for their practical use in real biological environments. Confinement refers to the spatial restriction of molecules, reactants, or reaction interfaces within nanometer-sized domains, where their physicochemical behaviors differ markedly from those in bulk solutions. Under confined conditions, reactive components can be shielded from external interference, thus enhancing molecular stability. Moreover, confined environments can locally enrich reactants and reduce the configurational entropy of reaction components, greatly improving the thermodynamic and kinetic efficiency of molecular interactions. Thus, integrating confinement effects into DNA nanodevices offers a promising strategy for the synergistically enhancing both structural robustness and sensing performance in complex biological samples. In this Account, we describe our recent efforts to design and develop spatially confined DNA nanodevices aimed at improving molecular sensing in real biological samples. By engineering the molecular interaction interface of DNA nanodevices through confinement strategies, we have developed four representative classes of such materials, that are cavity-confined, surface-confined, topological structure-confined, and network-confined DNA nanodevices. We systematically explore their advanced applications in biomarker sensing within biological samples and discuss the underlying mechanisms responsible for the enhanced structural stability and the analytical performance, including sensitivity, limit of detection, and reaction kinetics. The experimental progress summarized in this Account suggests that confinement strategy could serve as a versatile design principle for engineering DNA nanodevice interfaces, thereby advancing practical biosensing applications in complex biological environments.
Conspectus Preserving the structure, molecular information, and functional activity of biological systems across time remains a central challenge in modern biotechnology. Existing preservation strategies often involve trade-offs: approaches that maintain structural fidelity frequently compromise molecular integrity, whereas methods designed to stabilize biomolecules typically disrupt native architecture or function. Nature, however, provides compelling precedents for long-term biological preservation. Fossils recovered from Siberian permafrost have retained readable genetic material for millions of years, and silicified organisms frequently preserve detailed morphological features together with molecular chemical signatures embedded within mineral matrices. These natural examples suggest that silicification can simultaneously immobilize biological structures and stabilize core biomolecular information. However, fossilization is inherently slow, uncontrolled, and irreversible, unfolding over geological time scales. A key challenge therefore emerges: whether artificial, biomimetic silica shells can be engineered to capture and preserve biological systems with comparable fidelity but under controllable laboratory conditions and across practical time scales. In this context, silica-based encoding is used here to denote more than passive preservation: it converts biological structures, molecular information, and functional states into mineral-stabilized forms that remain readable and, in selected cases, recoverable. In this Account, we summarize recent advances in a controllable biomimetic silicification platform developed by our group that enables multilevel preservation of biological systems. At the structural level, silica replication produces high-fidelity three-dimensional preservation of biological architectures spanning subcellular organelles, individual cells, and complex tissues, overcoming the conventional compromise between morphological resolution and preservation stability. At the molecular level, in situ encapsulation within a silica matrix substantially enhances the chemical stability of biomacromolecules, allowing genomes, transcriptomes, and proteomes to be preserved at room temperature for extended periods without reliance on cryogenic storage. At the functional level, the approach extends beyond static preservation: enzymatic activity and cellular viability can be retained during encapsulation and subsequently restored after controlled silica removal, enabling the recovery of biological function from preserved samples. These capabilities arise from key physicochemical properties of silica matrices. Their high surface area and tunable chemical environment stabilize biomolecules through non-covalent interactions such as electrostatic attraction and hydrogen bonding, while the mild and controllable dissolution of silica enables on-demand decapsulation with minimal perturbation to molecular integrity and biological activity. Looking ahead, advancing this technology demands several key research directions. A deeper mechanistic understanding of silica precursor–macromolecule interactions will enable precise control over silicification pathways, facilitating their extension to complex biological systems and integrated multiomics preservation. Concurrently, developing standardized protocols compatible with clinical workflows and biobanks is critical for practical translation. These capabilities could drive novel strategies for long-term biospecimen storage, disease modeling, drug discovery, biosensing, and early biological system reconstruction. Ultimately, by enabling the controllable silica-based encapsulation of biological data, biomimetic silicification provides a powerful framework for preserving and reactivating life, potentially transforming how biological materials are archived, studied, and utilized across the life sciences.
Conspectus Excitons are mobile excited states in materials with properties and dynamics that underpin many applications of conjugated organic polymers. Understanding these quasiparticles in organic materials requires knowledge of classical molecular photophysics and solid-state physics-based descriptions of semiconducting polymers. The molecular interpretation of an exciton is an excited state with physical size determined by the region over which bond lengths/angles are relaxed from their equilibrium ground state geometries. The physics representation is that excitons are quasiparticles comprising a bound electron–hole pair. Specifically, in the excited state the hole is a vacancy in the HOMO (valence band) and the electron is an unpaired electron in the LUMO (conduction band). Excitons move through multiple mechanisms. These include Förster energy transfer wherein the dipole from a virtual electronic emission is captured by a coupled chromophore to create a new excited state. The Förster mechanism is facilitated by the natural tendency of the high aspect ratio of conjugated polymer chromophores to align, the relatively low dielectric constant of the materials, and the high spectral overlap of the absorptions and emissions. In a second mechanism, the exciton moves through band transport, wherein thermal phonons (traveling compression/expansion nuclear motion excitations) nudge the excitons and cause movement. This mechanism requires direct orbital interactions (strong electronic coupling) and is related to Dexter energy transfer in the molecular systems, wherein collisional interactions between molecules allow for energy transfer. Both molecular and solid-state physics perspectives are valuable in understanding exciton dynamics/mobility. Exciton transport is central to photovoltaics and photodetectors excitons wherein these electron–hole pairs diffuse to interfaces and separate to create electrical potentials and/or photocurrents. Ultrasensitive chemical sensors and biosensors based on conjugated organic polymers exhibit amplified sensor responses enabled by exciton diffusion. This natural amplification has been widely exploited for trace chemical and biological sensing, and explosive sensors have been commercial now for more than 20 years based on this principle. Moreover, the polychromophore character of conjugated organic polymers creates very large absorption cross sections and when combined with high emission quantum yields makes them exceptionally bright fluorescent labels, which has found use in biology. Exciton diffusion enhances photoredox catalysis wherein fast exciton diffusion increases the probably of encounter of the reactive excited state within a nanosecond timeline. My studies of excitons have been guided by classical physical organic chemistry wherein hypotheses are tested through materials design and synthesis. I will detail how receptor integration, control of interpolymer organization, precision assembly of aligned polymers, and modulation of excited state lifetimes have provided understanding and empowered key applications.
Molecular conformation is a fundamental determinant of intramolecular interactions, reactivity, and conjugation extent in organic molecules, directly influencing properties ranging from photophysical characteristics to chemical reactivity. Consequently, precise control over molecular conformation represents both a significant challenge and opportunity in organic chemistry and materials science, enabling the rational design of functional materials. Beyond covalent modifications such as steric group incorporation, molecular conformation can also be effectively regulated through noncovalent host-guest complexation in supramolecular chemistry. Among the various supramolecular tools available, the cucurbit[n]uril (CB[n], n = 5-8, 10) family of synthetic macrocycles has emerged as a powerful tool for conformational manipulation. CB[n] hosts feature rigid, hydrophobic cavities and electronegative carbonyl portals, providing excellent binding affinity and selectivity toward cationic guest molecules through a combination of hydrophobic effects, ion-dipole interactions, and hydrogen bonding. Larger homologues such as CB[7], CB[8], and CB[10] possess cavities capable of encapsulating and precisely manipulating molecular conformations through host-guest interactions, thereby profoundly altering guest properties. The evolution of CB[n] hosts from simple molecular containers to conformational regulators has enabled the construction of diverse functional supramolecular materials. Recently, numerous supramolecular assemblies have been developed through CB[n]-mediated conformational control.This Account provides an overview of recent fundamental advances and applications in CB[n]-mediated conformational control, establishing clear structure-property relationships between conformation manipulation and material functionality. We categorize CB[n]-mediated conformationally adaptive guest molecules into five representative paradigms, each demonstrating a distinct mode of conformational modulation: the induced U-shaped folding of flexible alkyl chains within the hydrophobic cavity, the folded conformation of charge-transfer complexes within CB[n], controllable photoresponsiveness of diarylethene molecular photoswitches, controlled twisting of sterically constrained molecules, and linear donor-acceptor type molecules. Through a careful evaluation of selected examples, we demonstrate that CB[n] functions as a conformational regulator rather than merely a molecular container with the confined microenvironment effectively shifting the conformation into normally disfavored states. More importantly, this complexation process yields host-guest systems with unique properties markedly different from the free guest molecules, including tunable fluorescence or room temperature phosphorescence (RTP) emission as well as different responsive behaviors toward light and external mechanical stimulation. We further explore the applications of CB[n]-mediated conformational control, including tunable luminescent materials for sensing and information encryption, efficient RTP materials for bioimaging, photochromic materials, mechanochromic materials, and stimuli-responsive biomaterials. Finally, this Account outlines the challenges and future perspectives for designing CB[n]-based systems with multiple functions. By integrating molecular design with diverse applications across chemistry, materials science, and bioimaging, this Account aims to deepen the understanding of supramolecular conformational engineering while inspiring broader efforts to translate CB[n]-mediated conformational control into advanced material functionalities.
Conspectus The relentless increase in power density and advancements in nanoengineering in modern electronic and energy conversion technologies have pushed thermal management to its physical limits, where ballistic transport phenomena and the wave nature of phonons become important. Our research tackles this frontier using a dual approach: advanced experimental tools to accurately probe thermal transport across ballistic and diffusive regimes, and predictive theoretical methods to resolve wave-based phonon transport with atomic precision. On the experimental front, transient thermal grating (TTG) spectroscopy has emerged as a crucial noncontact optical technique for probing complex material systems that are inaccessible to other methods, including new classes of materials such as two-dimensional (2D) covalent organic frameworks (COFs) and hybrid perovskites. Studying in-plane thermal transport in these materials is particularly challenging due to their small dimensions or fragility. On the theoretical front, the atomistic Green’s function (AGF) is a quantum-mechanical framework that describes phonon transport as wave propagation and accounts for interactions with the atomic structure, defects, and interfaces from first-principles, providing fundamental physical insights. This Account summarizes how we leveraged TTG and AGF for scientific discoveries. For instance, we used TTG to directly measure the in-plane thermal conductivity of novel 2D COFs, revealing a high value of ∼ 1.18 W/(m·K). We also applied TTG to unveil remarkably weak anisotropy of 1.5 in thermal conductivity of 2D hybrid perovskites. Furthermore, we developed TTG to uniquely characterize micrometer-thick metallic interfaces, smaller than the laser beam size. In the theoretical domain, we developed anharmonic AGF method for three-dimensional (3D) interfaces and discovered enhanced thermal interface conductance due to anharmonicity at the interface. We also found enhanced conductance due to a bridging effect caused by atomic mixing. We applied AGF to directly capture phonon Anderson localization in aperiodic superlattices and coherent phonon transport in periodic superlattices. The collective insights gained from these distinct experimental and theoretical advances are building a framework for the rational design of materials with tailored thermal transport properties, paving the way for next-generation solutions in electronics packaging, thermoelectrics, thermal insulation, and beyond.
Electrochemical biosensors hold promise for autonomous molecular monitoring owing to their sensitivity, electronic compatibility, and suitability for wearable, implantable, and point-of-care platforms. However, conventional operation relies on external calibration that erodes with batch-to-batch variability and environmental fluctuations, ultimately compromising long-term accuracy in complex biofluids and in vivo environments. Calibration-free electrochemical sensing addresses this challenge through three complementary strategies. First, intrinsic dual-signal encoding strategy embeds two distinct redox-reporters to generate ratiometric outputs that convert absolute faradaic currents into self-normalized readouts, thereby eliminating the need for external calibration. Second, operationally programmed self-referencing strategy extracts drift-differentiated kinetics from a single reporter by varying measurement parameters or environmental conditions. Third, interfacial engineering slows signal decay and drift at its molecular origin through coordinated optimization of redox reporters, self-assembled monolayers, protective layers and nuclease-resistant nucleic-acid scaffolds. This Account summarizes recent advances, outlines these signal- and interface-level designs and their principles, and discusses opportunities toward long-lasting autonomous biosensing in clinical settings.
Iron oxide (nano)minerals are abundant and reactive components of natural systems, exerting a profound influence on the environmental fate of contaminants. Among these, pharmaceutical pollutants have gained increasing attention due to their ubiquitous presence in aquatic and terrestrial environments, their persistence, and their potential to harm ecosystems and human health, particularly through contributions to antimicrobial resistance.Iron oxides play a dual role in mitigating pharmaceutical pollution: they serve as adsorptive surfaces and as redox-active materials capable of transforming pharmaceutical compounds. Adsorption is governed by the affinity between pharmaceutical functional groups and specific iron oxide surface sites, while redox-active pharmaceuticals may undergo abiotic transformations upon electron transfer with Fe(III) or mixed-valent (Fe(II)-Fe(III)) minerals. These interactions can yield breakdown products with altered bioactivity and toxicity, adding complexity to environmental risk assessments. However, these processes remain poorly understood due to experimental limitations and the absence of reliable predictive models. Predicting pharmaceutical behavior under environmentally relevant conditions requires bridging multiple spatial and temporal scales.In this Account, we provide a multiscale evaluation of how iron oxides influence the fate and remediation potential of pharmaceutical pollutants, integrating findings from experimental and modeling studies at molecular, interface, pore, column, and field levels. We also explore how Machine Learning can link across scales and uncover emergent patterns in complex data sets. Environmental factors, including solution chemistry, mineral properties, and co-occurring components, significantly influence these interactions.This approach allows us to identify key knowledge gaps, draw connections between molecular-scale reactivity and macroscale environmental processes, and highlight opportunities for developing predictive tools for environmental risk assessment. The insights gained extend beyond pharmaceuticals to a wide range of emerging organic contaminants. Advancing this field requires interdisciplinary collaboration at the intersection of molecular geochemistry, environmental materials science, mineralogy, hydrology, and microbiology.
Circularly polarized luminescence has emerged as a cutting-edge research field owing to its dual significance in advancing the fundamental understanding of chiral excited states and enabling the design of novel functional materials. A central challenge in realizing efficient CPL lies in the effective integration of chirality with the luminescent moieties. Conventional strategies, often based on covalent bonding between chiral and luminescent units in small molecules, frequently lead to systems that show either no or only weak CPL. Meaningfully, supramolecular assembly offers a transformative alternative by facilitating chiral transfer and amplifying the CPL signals. In a broader context, supramolecular assembly serves as a foundational methodology for constructing macroscopic functional supramolecular architectures from molecular-scale building blocks. More importantly, by regulating noncovalent interactions, supramolecular approaches enable efficient chirality transfer from chiral sites to assembled luminescent architecture, even allowing achiral luminophores to display stronger CPL activity through simple mixing or doping. Moreover, such an assembled architecture can significantly enhance CPL intensity, greatly broadening the scope of high-performance CPL-active materials.Macrocycles are fundamental to supramolecular chemistry owing to their critical roles in molecular recognition. However, most macrocycles are intrinsically achiral or exhibit poor chirality in their isolated molecular state, posing a significant challenge for effective integration of chirality with luminophores and subsequent amplification of CPL. This Account presents an innovative strategy to address this issue through a hierarchical confinement effect at both molecular and supramolecular assembly levels. We demonstrate how chirality can be introduced or transferred within a macrocycle-based hierarchical assembled architecture to generate and enhance CPL signals. Key advances discussed include the successful induction and propagation of chirality via hierarchical assembly of the macrocyclic supramolecular architecture under a multiple confinement effect, leading to efficient activation and substantial amplification of CPL within the supramolecular system. Specific approaches encompass (1) steering CPL by organizing macrocycles into helical architecture for supramolecular chirality induction, transfer, and signal amplification; (2) tuning CPL through spatial confinement of achiral luminophores within chiral inner cavities of the hierarchical macrocyclic assembled architecture; and (3) modulating CPL via macrocycle outward surface-mediated coassembly of guests for precise control of the morphology and CPL. Collectively, these multiple confinement effects establish a systematic framework for manipulating the chiroptical properties of the hierarchically assembled nanoarchitectures. Beyond advancing the fundamental understanding of chiral luminescence, these methodologies enable the rational design of high-performance CPL-active materials.
Biological membranes constitute the fundamental scaffolding of life, serving as sophisticated interfaces that drive cellular function through the spatial compartmentalization of functional units. They integrate enzymatic catalysis, molecular recognition, and regulated transport within finely tuned microenvironments, ensuring exceptional efficiency, selectivity, and resilience in biological conversion networks. Translating these advantages beyond native biological contexts remains a central objective in chemical manufacturing, biotechnology, and biomedicine. However, the inherent fragility of enzymes and living cells outside physiological environments, combined with the mismatch between the survival-oriented nature of biological systems and the performance-driven requirements of industrial manufacturing, hinders their broader application. Therefore, bridging the biological sophistication with industrial rigor necessitates the development of programmable synthetic platforms capable of re-encoding these membrane-inspired principles into robust and functional material architectures.Covalent organic frameworks (COFs), featuring long-range-ordered structures, finely tunable nanochannels, high porosity, and chemically tailorable frameworks, offer a compelling platform to address this challenge. Their molecular-level programmability enables precise control over pore sizes and interfacial chemistry, allowing for the construction of confined microenvironments commensurate with biomacromolecules. Beyond serving as immobilization supports, the structural precision of COFs enables function-driven biomimetic engineering. Deeper investigations into biointegration strategies and membrane-mimetic design within COFs are essential for advancing next-generation catalytic, energy, and biomedical materials.In this Account, we summarize our group's efforts to bridge biological function with COF design along two complementary directions. First, we develop COF-based biointegrated confined microreactors that engineer membrane-inspired catalytic environments for enzymes and living cells. By tailoring confinement dimensions, engineering hydration-like microenvironments, and modulating covalent anchoring interactions, COFs create protective yet tunable nanoscale compartments that stabilize biomacromolecules and optimize their conformations. The assembly of selective transport channels at biointerfaces further enables efficient substrate exchange while excluding detrimental species, extending biocatalysis into harsh or non-native environments. Importantly, these confined architectures further support functional expansion toward continuous-flow operation, multienzyme, and chemoenzymatic cascade systems, transforming isolated biological components into versatile, integrated catalytic platforms. Second, moving beyond biointegration, we demonstrate that COFs can be designed to emulate core structural and functional attributes of biological membranes. Through hydrophilicity-gradient nanochannels, adaptive linkage chemistries, and spatially defined binding pockets, COFs can encode directional transport, hydration regulation, and selective molecular recognition directly into crystalline porous frameworks. Finally, we discuss current challenges and outline future opportunities toward intelligent, adaptive biomimetic architectures. It is expected that this Account would provide an understanding of structure-function relationships in membrane-inspired COF engineering and inspire the development of next-generation biointerfaces for catalysis, energy conversion, environmental remediation, and biomedical technologies.
