Yichun Wang

Selectively perturbing pathogenic membranes while preserving host-cell integrity is a fundamental challenge in the design of membrane-active biomaterials. This challenge is particularly acute for enveloped viruses because their lipid membranes are derived from host cells and therefore share many of the same molecular constituents. Here, we demonstrate that engineered nanochirality provides a structural parameter for distinguishing virus-organized membrane nanodomains from host-cell membranes. Histidine-functionalized graphene quantum dots (His-GQDs) form enantiomeric nanoscale structures with distinct interfacial topologies despite closely matched size, composition, and surface charge. D -His-GQDs preferentially interact with cholesterol-rich ordered membrane nanodomains associated with S-acylated coronavirus Spike, penetrate more deeply into raft-like lipid bilayers, and induce lipid disordering, membrane leakage, and viral-envelope disruption. Reducing Spike S -acylation or depleting membrane cholesterol attenuated this stereoselective interaction, while molecular simulations revealed asymmetric lipid organization surrounding S -acylated Spike and preferential insertion of D -His-GQDs into the ordered membrane environment. Functionally, D -His-GQDs directly inactivated human coronavirus OC43 (HCoV-OC43), inhibited infection with an EC50 of 0.92 μg mL□ ¹ and exhibited a selectivity index of 361. Stereoselective antiviral activity extended to human cytomegalovirus, demonstrating activity across distinct enveloped-virus families, and intranasal D -His-GQDs protected HCoV-OC43-challenged mice under both prophylactic and early post-exposure regimens. Overall, these findings establish structural nanochirality as a biomaterial design parameter for recognizing higher-order membrane organization and converting virus-associated membrane states into selectively addressable therapeutic vulnerabilities.

Chirality offers a powerful but underdeveloped design principle for regulating the optical, molecular, and biological behavior of carbon nanomaterials. Unlike small molecules, whose handedness is typically defined by discrete stereocenters, carbon nanomaterials can encode chirality across multiple structural domains, including the carbon framework, chemically accessible surfaces and interfaces, and supramolecular assemblies. These domain-encoded chiralities differ in how they are generated, how they produce chiroptical and electronic responses, and how they are presented at nano–bio interfaces. In this Review, we organize chiral carbon nanomaterials, including carbon dots, graphene quantum dots, graphene oxide derivatives, carbon nanotubes, fullerenes, graphene nanoribbons, and hybrid assemblies, into framework-encoded, surface/interface-derived, and supramolecular chirality. We examine how each category produces circular dichroism, circularly polarized luminescence, fluorescence, and electronic responses, and how these properties influence biointerface interactions and biological or bioanalytical functions. Representative studies span molecular recognition, sensing and imaging, membrane and extracellular-matrix transport, drug delivery, and selected therapeutic effects, including phototherapy, antimicrobial activity, and protein-homeostasis regulation. We further identify major barriers to predictive design, including limited structural control, incomplete assignment of chiroptical origins, insufficient separation of chirality effects from nonchiral physicochemical variables, and limited validation in realistic biological environments. By connecting structural origin, optical expression, and biointerface effect, this Review provides a framework for mechanistically interpreting and designing chiral carbon nanomaterials for biological and bioanalytical applications.

Immunotherapy has transformed cancer treatment, yet cell-based therapies remain complex and costly, and immune checkpoint blockade (ICB) agents often suffer from limited stability and poor T-cell selectivity. Here, we develop an engineered dendritic cell–derived small extracellular vesicle (DC-sEV) nanoplatform for combinatorial immunotherapy via in situ T-cell activation and checkpoint reprogramming. DC-sEVs preserve intrinsic dendritic-cell immunobiology, enabling antigen presentation and potent T-cell activation. We further integrate high-efficiency cargo loading and membrane functionalization to selectively deliver ICB payloads to T cells, achieving dual reprogramming that sustains effector function and amplifies antitumor immunity. This approach reduced cancer cell viability to 44.05% in vitro and produced 82.12% tumor growth inhibition in vivo , establishing DC-sEVs as a targeted, scalable cell-free immunotherapy platform. HIGHLIGHTS: DC-sEVs preserve antigen presentation, T-cell activation, and lymph node targeting Chirality-assisted loading with pH-responsive functionalization enables efficient cytosolic delivery while maintaining membrane bioactivity Engineered DC-sEVs combine in situ T-cell priming and PD-1 silencing to enhance effector function In situ T-cell reprogramming drives potent antitumor efficacy and favorable tumor microenvironment remodeling GRAPHICAL

Macrophage small extracellular vesicles (sEVs) carry phenotype-linked cargo and bioactivity for immunomodulation and regeneration, but therapeutic translation is limited by low secretion and poor control of function. We introduce a music-activated piezoelectric nanofiber substrate (PES) that converted audible sound into programmable electrical stimulation to enhance sEV biogenesis while tuning macrophage polarization. Adjusting acoustic parameters increased sEV yield, while musically inspired “assemblies” biased macrophage phenotypes: dissonant, low-frequency stimuli promoted M1-like inflammation, whereas consonant, higher-frequency stimuli favored M2-like, regenerative states. These shifts produced distinct sEV cargo and bioactivities. We rationally designed customized music stimulus that maximized both vesicle production and M2 bias, yielding sEVs exhibited regeneration potentials. This work establishes a programmable acoustic–piezoelectric strategy to scale macrophage sEV production while tailoring their therapeutic potency.

Cellular 3D cancer spheroid technologies are novel tools that facilitate large-scale drug screening to bridge the in vitro–in vivo gap, without the cross-species effects of animal models. However, many spheroid studies fail to achieve IC50 (dosage for 50% inhibition) even for unreasonably high applied drug concentrations (up to 1000× 2D IC50). By mapping oxygen transport in patient-derived pancreatic cancer spheroids, this limiting viability is attributed to a near-universal oxygen decay gradient that renders cells deeper than 20 μm from the spheroid surface hypoxically quiescent and resistant to many chemotherapeutic drugs. The dose-independent viability barrier prevents IC50 from being achieved for spheroids larger than 150 μm in diameter if the applied drug is dependent on the proliferating cell behavior. By examining three cancer cell types and five chemotherapeutic drugs, targeting this limiting viability barrier allows the selection of drugs and adjuvants that are effective in treating all cell populations within a spheroid. The reported analysis provides a framework for the accurate assessment of drug efficacy to target both well-oxygenated proliferating cells and hypoxically quiescent cells in biologically relevant and realistic 3D spheroid systems.

Small extracellular vesicles (sEVs) have emerged as next‐generation multifunctional nanotherapeutics due to their parental‐cell traits and role in intercellular communication. Among them, immune cell–derived sEVs are uniquely positioned to couple innate immunomodulatory activities with therapeutic payload delivery, making them highly attractive for cancer therapy. In particular, M1 macrophage‐derived sEVs (M1‐sEVs) preserve the tumour‐suppressive functions of their parent cells, including tumour microenvironment (TME) reprogramming, immune activation, and inhibition of cancer progression. However, the mechanisms by which these activities are coordinated within the TME, and whether they act independently or synergistically, remain poorly understood. Clarifying these mechanisms is crucial for harnessing their intrinsic bioactivity in combination with their natural capacity as drug delivery nanocarriers to optimize therapeutic efficacy. Here, we demonstrate that M1‐sEVs exhibit intrinsic stability and circulation longevity via ‘do not eat me’ ligands, as well as tumour‐homing ability revealed by proteomic profiling, enabling efficient uptake and deep infiltration in breast cancer models. Functionally, M1‐sEVs deliver antiproliferative microRNAs that suppress tumour metabolism, growth, and progression by inhibiting self‐renewal, adhesion, migration, motility, and invasion. Importantly, by integrating this endogenous bioactivity with exogenous doxorubicin loading, we achieved synergistic efficacy: a 3‐fold reduction in IC ₅₀ in vitro (0.46 µM vs. 1.45 µM for free drug) and 70.18% tumour growth inhibition in vivo. These findings highlight M1‐sEVs as dual‐action nanotherapeutics that combine innate immune‐regulatory and tumour‐inhibitory functions with efficient drug delivery, advancing their development as powerful platforms for cancer therapy.

Chirality in two-dimensional nanomaterials provides a powerful lever to control biological interfaces, yet the structural origins of nanoscale chirality remain poorly understood. Here, we systematically investigate chiral ligand modulated graphene quantum dots (GQDs) and reveal how ligand stereochemistry and edge chemistry modulate the formation of diverse chiral or achiral nanostructures. Spectroscopy, microscopy, and density functional theory with ring-puckering analysis identified six structural motifs, twisted-, twisted-boat, saddle-shaped, hybrid, unbuckled, and random. Among these, twisted-, twisted-boat, and saddle-shaped GQDs exhibited genuine nanoscale structural chirality, while unbuckled, hybrid, and random conformations lacked organized distortion. Importantly, structural chirality governed passive permeation into biological membrane (e.g. lipid membrane of extracellular vesicles), whereas achiral variants relied mainly on hydrophobic interactions. In contrast, active transport across biological membrane (e.g. endocytosis) is insensitive to nanoscale structural chirality but strongly influenced by chiral ligand identity and transporter recognition. Collectively, these results establish chiral ligand conjugation as a modular route to program both chiral and achiral motifs in graphene nanostructures and highlight nanoscale structural chirality as a design principle for engineering bio-nano interactions.

Small extracellular vesicles (sEVs) have emerged as next-generation multifunctional nanotherapeutics due to their parental-cell traits and role in intercellular communication. Among them, immune cell–derived sEVs are uniquely positioned to couple innate immunomodulatory activities with therapeutic payload delivery, making them highly attractive for cancer therapy. In particular, M1 macrophage-derived sEVs (M1-sEVs) preserve the tumor-suppressive functions of their parent cells, including tumor microenvironment (TME) reprogramming, immune activation, and inhibition of cancer progression. However, the mechanisms by which these activities are coordinated within the TME, and whether they act independently or synergistically, remain poorly understood. Clarifying these mechanisms is crucial for harnessing their intrinsic bioactivity in combination with their natural capacity as drug delivery nanocarriers to optimize therapeutic efficacy. Here, we demonstrate that M1-sEVs exhibit intrinsic stability and circulation longevity via ‘do not eat me’ ligands, as well as tumor-homing ability revealed by proteomic profiling, enabling efficient uptake and deep infiltration in breast cancer models. Functionally, M1-sEVs deliver antiproliferative microRNAs that suppress tumor metabolism, growth, and progression by inhibiting self-renewal, adhesion, migration, motility, and invasion. Importantly, by integrating this endogenous bioactivity with exogenous doxorubicin loading, we achieved synergistic efficacy: a 3-fold reduction in IC ₅₀ in vitro (0.46 μM vs. 1.45 μM for free drug) and 70.18% tumor growth inhibition in vivo . These findings highlight M1-sEVs as dual-action nanotherapeutics that combine innate immune-regulatory and tumor-inhibitory functions with efficient drug delivery, advancing their development as powerful platforms for cancer therapy.