Hongping Zhou

Multiphoton fluorophores are typically based on extended π-conjugated architectures, resulting in structural complexity and limited tunability. Here, we report a chirality-guided strategy for constructing high-order multiphoton fluorophores from a minimalist single-aryl scaffold. Through solvent-assisted assembly, chirality and hydrogen-bonding interactions organize heteroatoms into ordered chiral heteroatom clusters (CHCs), enabling through-space conjugation and clusteroluminescence without direct aryl–aryl π–π stacking. Structural and chiroptical studies reveal that chirality is encoded into the emissive cluster states and governs clusteroluminescence. Donor–acceptor engineering further establishes CHC-mediated through-space charge transfer in which heteroatom clusters act as electronic bridges connecting spatially separated donor and acceptor units. The synergistic interplay between chirality-guided CHC organization and charge transfer enhances electronic delocalization and polarizability, leading to efficient two-, three-, and four-photon-excited fluorescence in an isolated aromatic framework. The enhanced nonlinear optical response enables deep imaging of three-dimensional tumor spheroids with penetration depths up to 160 μm. This work establishes chirality-guided heteroatom clustering as a general strategy for compact multiphoton fluorophores and nonlinear optical materials.

The trade‐off between fluorescence imaging and photosensitization capability of pentamethine cyanine (Cy5) has greatly impeded its applications in phototherapy. Molecular design strategy has been the prevailing way to enhance its ROS generation efficiency, yet still unsatisfactory in the synergistic optimization of the synthesis procedure and the charge separation (CS) efficiency. Herein, by the incorporation of the stereo‐π anion BPh ₄ ⁻ into a series of Cy5 skeletons, the ROS generation capability was enhanced by 8 times, and an efficient oxygen‐independent electron transfer pathway was evoked, unlocking the long‐lived charge‐separated state (CSs) and favoring photodynamic immunotherapy. The “End to End” stacked Cy5‐BPh ₄ ensured weak electronic coupling (V) and a higher driving force for blocking charge recombination (CR), ultimately unfolding its efficient CS to facilitate subsequent electron transfer pathways. The superior ROS production in Cy5‐BPh ₄ conferred potent phototoxicity against hypoxic cancer cells and elicited immunogenic cell death responses, achieving excellent antitumor efficacy in both primary and distant tumors. Overall, this work delivered a universal paradigm to endow cyanine‐PSs with long‐lived CSs for antitumor photodynamic immunotherapy.

The development of organic materials capable of simultaneously exhibiting circularly polarized luminescence (CPL) and high‐order multiphoton excited fluorescence (H‐MPEF) is highly desirable for near‐infrared (NIR) imaging and sensing of chiral microenvironments in biomolecular systems, yet remains a significant challenge. Herein, we report a facile chiral assembly strategy that enables concurrent CPL and three‐photon excitation fluorescence (3PEF) through the interaction of achiral pyridinium‐based homodimers with calf thymus DNA ( ct DNA). Specifically, two homodimers, designated LD and FD , were precisely designed and synthesized to feature distinct spatial configurations. The linear LD , with its narrow molecular thickness, binds preferentially to the minor groove of ct DNA via electrostatic interactions. This association facilitated efficient chirality transfer from the DNA scaffold while simultaneously triggering 3PEF through effective suppression of nonradiative decay, ultimately yielding a pronounced CPL signal. Collectively, this work not only provided a viable strategy for designing achiral small organic molecules compatible with nucleic acid but also elegantly addresses the longstanding challenge of achieving integrated CPL and NIR‐window fluorescence imaging.

An unsymmetrical 1,4-difunctionalization of C60 using H-phosphonates and nucleophiles─which involves a one-pot stepwise process of nucleophilic addition, protonation, and oxidative coupling─has been developed for the synthesis of a wide range of 1,4-(phosphonyl)(organo)[60]fullerenes. Furthermore, a cascade pathway involving fullerene anions and fullerene radicals leading to 1,4-diorgano-[60]fullerenes has been revealed by the capture of the phosphonate-substituted fullerene radical by BHT.

Aggregation-induced emission (AIE)-active fluorescent nanoprobes for lipid droplets (LDs) have great potential for monitoring the physiological dynamic evolution of LDs due to their high biocompatibility and excellent photostability. However, hydrophobic LDs probe exhibit weak intermolecular interactions in aqueous media, which usually leads to disordered spontaneous aggregation and uncontrollable microstructure, thereby restricting the controllable fabrication of high-performance LDs fluorescent organic nanoprobes (FONs). To address this issue, an AIE-active probe CPB-BTH-Hex with solvent polarity sensitivity was rationally constructed via a molecular engineering strategy. By improving molecular planarity, the intermolecular π···π interactions were effectively strengthened, enabling the formation of highly ordered pre-aggregates before encapsulation and achieving precise regulation of aggregate morphology and structure. Single-crystal structure analysis reveals that the probe adopts J-aggregation in the crystalline state, but accompanied by blue-shifted in absorption and emission spectra. Theoretical calculations combined with detailed spectroscopic investigations reveal that the probe form aggregates with magic-angle stacking in DMSO/H₂O mixtures containing a moderate water fraction. Meanwhile, the twist intramolecular charge transfer (TICT) featuring by overall molecular distortion and local parallel alignment arises from variations in molecular torsional angles, combined with magic-angle stacking collectively account for the AIE behavior of the probe in aqueous media, endowing it with a unique fluorescence enhancement effect. After encapsulation with poly(lactic-co-glycolic acid) (PLGA), the resulting nanoprobe exhibits excellent bioimaging performance. It realizes long-term and stable dynamic tracking of intracellular LDs and clearly visualizes the fusion and fission processes of LDs in living cells, providing a reliable visual tool for exploring the biological functions of lipid droplets.

Homogeneous oxygen reduction reaction (ORR) studies rely on two predominant electron delivery modes, yet a critical solvent mismatch between electrochemically (aqueous) and chemically (nonaqueous) driven assays invalidates cross-system comparisons of catalytic activity and selectivity for Cu-based molecular catalysts. Herein, we compare ORR catalysis by two pyridinophane-copper(II) complexes, [Cu^tmpa-NH]²⁺ and [Cu^bmpa-NH]²⁺, under matched conditions to evaluate the intrinsic influence of electron delivery modes. Both follow an overall third-order rate law (first-order dependences on [catalyst], [O₂], [acid]) in acetonitrile. However, [Cu^tmpa-NH]²⁺ exhibits 40-fold higher activity and near-exclusive four-electron selectivity (96.42% H₂O), whereas [Cu^bmpa-NH]²⁺ displays mixed two-electron/four-electron behavior (58.22% H₂O₂). Critically, [Cu^tmpa-NH]²⁺ maintains consistent four-electron selectivity and activity across both electron delivery modes, confirming that its intrinsic ORR performance is independent of the electron delivery mode and governed solely by its coordination sphere. This work identifies an easily overlooked issue in chemical ORR assays: decamethylferrocene reacts with in situ formed H₂O₂ in acidic media, interfering with selectivity and kinetic analysis. Notably, a centrosymmetric bis(μ–OH)-bridged dinuclear Cu(II) intermediate generated from the reaction of [Cu^bmpa-NH]⁺ with O₂ has been successfully isolated and structurally characterized. Overall, this work establishes a structure–activity-selectivity relationship for pyridylamine-copper ORR catalysts and provides rational design guidance for their high-performance analogues.

The therapeutic efficacy of iron oxide nanozymes in cancer catalytic therapy has been severely constrained by the insufficient endogenous H ₂ O ₂ . To address this, constructing a self–cascading nanozyme that integrates oxidase (OXD) and peroxidase (POD) activities is highly desirable yet challenging, primarily due to the difficulty in stabilizing high–content of Fe(II) within nanostructures. Herein, we report the first synthesis of mesoporous amorphous iron oxide nanospheres (aFeO _x ‑N) with unprecedented high Fe (II) level (66.59%) via the confinement coordination strategy using the strong N–donor metformin. This unique structure simultaneously exhibits robust OXD–like activity for in situ H ₂ O ₂ generation via a 2e ⁻ oxygen reduction pathway and enhanced POD–like activity for consequent •OH production. In vitro studies verified the aFeO _x ‑N‑ss‑SiO ₂ (encapsulated by SiO ₂ outlayer containing ─S─S─ bonds for TME responsiveness) triggered ferroptosis and prominent cell death even under hypoxic conditions. Remarkably, a single ultralow dose (5 mg·kg ⁻¹ ) achieves a tumor inhibition rate of up to 96.19% in murine models, demonstrating exceptional therapeutic efficacy and biocompatibility. This work provides a novel and potent nanozyme platform for cascade catalytic tumor therapy.

The therapeutic efficacy of iron oxide nanozymes in cancer catalytic therapy has been severely constrained by the insufficient endogenous H ₂ O ₂ . To address this, constructing a self–cascading nanozyme that integrates oxidase (OXD) and peroxidase (POD) activities is highly desirable yet challenging, primarily due to the difficulty in stabilizing high–content of Fe(II) within nanostructures. Herein, we report the first synthesis of mesoporous amorphous iron oxide nanospheres (aFeO _x ‑N) with unprecedented high Fe (II) level (66.59%) via the confinement coordination strategy using the strong N–donor metformin. This unique structure simultaneously exhibits robust OXD–like activity for in situ H ₂ O ₂ generation via a 2e ⁻ oxygen reduction pathway and enhanced POD–like activity for consequent •OH production. In vitro studies verified the aFeO _x ‑N‑ss‑SiO ₂ (encapsulated by SiO ₂ outlayer containing ─S─S─ bonds for TME responsiveness) triggered ferroptosis and prominent cell death even under hypoxic conditions. Remarkably, a single ultralow dose (5 mg·kg ⁻¹ ) achieves a tumor inhibition rate of up to 96.19% in murine models, demonstrating exceptional therapeutic efficacy and biocompatibility. This work provides a novel and potent nanozyme platform for cascade catalytic tumor therapy.

Developing therapeutic agents that are capable of directly damaging nuclear DNA is critical for curing metastatic breast cancer. Herein, an enzyme‐mediated nuclear DNA‐targeted photogenerator ( P‐NO ₃ ) was constructed through dual‐key gating for amplified photodynamic immunotherapy (PDIT) against breast cancer, which has rarely been reported. Specifically, bilateral pyridinone units were included in the design to interact with overactivated cyclin‐dependent kinases 4 and 6 (CDK4/6) within breast cancer cells, which can circumvent the limitation of an impermeable nuclear envelope (the first key). Once inside the nucleus, the equipped dual‐positive pyridine groups can further competitively bind with DNA, promoting P‐NO ₃ to precisely anchor and illuminate nuclear DNA (the second key). Upon cascade activation, P‐NO ₃ utilized photogenerated highly toxic hydroxyl radical (·OH) in situ to damage the nucleus even under hypoxia, causing the up‐regulated expression of related genes (DDI2, KDM4D, RGCC). Concomitantly, damage‐associated high‐mobility group box 1 (HMGB1) and calreticulin (CRT) were released, triggering a systemic immune response to further suppress distant tumors, realizing efficient PDIT for breast cancer. This study provides new insight into designing nuclear‐DNA‐targeted phototherapeutic agents for complete ablation of metastatic tumors.