Yong Zhong

Glioblastoma is one of the most aggressive brain cancers with poor prognosis. Photodynamic therapy (PDT) is an efficient and noninvasive strategy for glioblastoma treatment. Porphyrins represent common photosensitizers for PDT but suffer from poor water solubility and low reactive oxygen species (ROS) yield. Herein, we report a porphyrin photosensitizer with enhanced ROS via a cascade fabrication involving the self-assembly of zinc meso-tetra(4-pyridyl)porphyrin (ZnTPyP) into tetragonal nanorods (NRs), followed by a polarity-driven morphological transition into hexagonal nanowires (NWs). Spectroscopic monitoring revealed a continuous disassembly-reassembly mechanism for this morphological transition, with a critical transition observed at 40% (v/v) ethanol. Different from the monoaxial Zn–N coordination and symmetric π-stacked structure of tetragonal NRs, the hexagonal NWs adopt a dual axial coordination and J-aggregated conjugated packing to form open hexagonal channels. This structural reorganization of NWs was accompanied by a significant absorption redshift, enhanced light harvesting, and a 1.9-fold increase in ROS generation. Upon 635 nm irradiation, the NWs exhibited a superior photodynamic effect (79.9%) compared to that of tetragonal NRs (44.5%). Apolipoprotein E (ApoE)-modified NWs traversed the blood-brain barrier and efficiently inhibited glioma growth in an orthotopic glioma model via enhanced PDT. Collectively, the solvent polarity modulation offers a powerful and general strategy to engineer supramolecular assembly architectures, paving the way for advanced photoactive nanotheranostics against brain diseases.

Single-cell–level resolution tumor therapy represents an advanced strategy against glioblastoma but lacks suitable theranostic agents. Here, we developed a spatiotemporal-switchable, two-dimensional (2D), bismuthene-based second near-infrared window (NIR-II) nanozyme. In this platform, the bismuthene scaffold simultaneously directed the assembly of indocyanine green (ICG) into ordered J -aggregates and anchored monodispersed platinum (Pt) atoms. The resulting J -aggregates acted as an optical antenna with a long-wavelength absorption peak at 895 nanometers and high photobleaching resistance of 78.0%, enabling the identification of single tumor cells with a resolution of 44.3 micrometers at 1350 nanometers for precise glioma resection. Postoperatively, the spatiotemporal-switchable function was activated for therapeutic intervention, in which the photothermal effect amplified the original efficiency of the catalase-like activity of Pt atoms by threefold, driving a surge in intracellular oxygen to combat tumor hypoxia. Upon 808-nanometer irradiation, the induced oxygen release in the tumor microenvironment amplified ICG-mediated photodynamic therapy, and combined with bismuthene-mediated photothermal therapy, it effectively inhibited residual tumors. In an orthotopic glioma mouse model, this approach minimized recurrence and achieved increased survival without inducing neurological or motor deficits. This work provides an atomic-level and molecular-level design blueprint for NIR-II nanotheranostic agents, paving the way toward clinical translation of single-cell–level precision medicine for brain malignancies.

Near-infrared (NIR) fluorescence probes featuring ultralarge Stokes shifts and efficient aggregate-state luminescence are highly desirable for bioimaging yet remain scarce due to formidable synthetic challenges and intricate photophysical modulation. We report a facile one-step click reaction to synthesize a tetracyanoquinodimethane-derived NIR probe (TNQ2) that overcomes the long-standing nonfluorescence limitation while achieving an unprecedented 445-nanometer Stokes shift. TNQ2 self-assembles into the smallest-sized two-dimensional J -aggregates (sub-160 nanometers) with a red-shift absorption from 545 to 725 nanometers and aggregation-enhanced emission around 1000 nanometers. The radiative/nonradiative modulation balances the fluorescence/photothermal/photodynamic effect to support high-sensitivity NIR-II fluorescence imaging-guided precise glioma resection and postoperative phototherapy to substantially extend survival in orthotopic glioma models. Our molecule/nanoengineering strategy establishes a transformative paradigm for developing advanced NIR phototheranostics for brain diseases.

Achieving precise control over the construction of efficient charge transport channels through self-assembly engineering represents a highly effective strategy for the synthesis of organic supramolecular photocatalysts. Herein, tetragonal zinc meso-5,10,15,20-tetra(4-pyridyl) porphyrin (ZnTPyP) nanorods (T-ZnTPyPs) and hexagonal ZnTPyP nanowires (H-ZnTPyPs) were synthesized by varying the assembly temperature. H-ZnTPyPs demonstrated a photocatalytic hydrogen production rate (183 mmol/g/h) that was 14.62 times greater than that of T-ZnTPyP (13 mmol/g/h). This significantly enhanced activity is primarily attributed to the distinct and well-defined molecular arrangements of H-ZnTPyPs, which support continuous linear long-range electron transfer pathways through effective π-π stacking. Conversely, the heat manipulation used in the synthesis of T-ZnTPyPs limits the participation of water molecules in the crystalline stacking arrangements, leading to lattice distortions that disrupt the π-π stacking interactions and significantly impede long-range electron transfer pathways. This research presents a novel strategy for modulating π-π stacking to optimize charge transport in supramolecular photocatalysts.

Glioblastoma is the most common and devastating brain tumor owing to its high invasiveness and high-frequency drug resistance. Near infrared-II (NIR-II) imaging-guided phototherapy based on polymer luminogens provides a promising remedy against drug-resistant glioma, but it is difficult to maximize photoenergy utilization. Herein, we designed a series of semiconducting polymers to boost the visualization and ablation of glioblastoma. By subtly engineering the side chains or substituents on the phenothiazine and thiophene moieties, an NIR-II polymer luminogen with high-quality fluorescence performance, good solubility, superior photothermal conversion, and balanced reactive oxygen species generation is achieved. The optimal polymer possesses a branched alkyl chain and tetraphenylethylene pendant to manipulate the equilibrium between the radiative and nonradiative energy-dissipating channels. High-sensitivity NIR-II imaging was used to monitor the blood-brain barrier penetration and glioma cell targeting of apolipoprotein E-modified polymer nanoparticles. The NIR irradiation triggers and maximizes the photon utilization in prominent photodynamic/photothermal synergistic therapy in orthotopic drug-resistant glioblastoma.

Currently used drugs for glioblastoma (GBM) treatments are ineffective, primarily due to the significant challenges posed by strong drug resistance, poor blood-brain barrier (BBB) permeability, and the lack of tumor specificity. Here, we report two cationic fluorescent anticancer agents (TriPEX-ClO₄ and TriPEX-PF₆) capable of BBB penetration for efficient GBM therapy via paraptosis and ferroptosis induction. These aggregation-induced emission (AIE)-active agents specifically target mitochondria, effectively triggering ATF4/JNK/Alix-regulated paraptosis and GPX4-mediated ferroptosis. Specifically, they rapidly induce substantial mitochondria-derived vacuolation, accompanied by reactive oxygen species generation, decreased mitochondrial membrane potential, and intracellular Ca²⁺ overload, thereby disrupting metabolisms and inducing nonapoptotic cell death. In vivo imaging revealed that TriPEX-ClO₄ and TriPEX-PF₆ successfully traversed the BBB to target orthotopic glioma and initiated effective synergistic therapy postintravenous injection. Our AIE drugs emerged as the pioneering paraptosis inducers against drug-resistant GBM, significantly extending survival up to 40 days compared to Temozolomide (20 days) in drug-resistant GBM-bearing mice. These compelling results open up new venues for the development of fluorescent anticancer drugs and innovative treatments for brain diseases.

Photoactive artificial nanocatalysts that mimic natural photoenergy systems can yield clean and renewable energy. However, their poor photoabsorption capability and disfavored photogenic electron–hole recombination hinder their production. Herein, we designed two nanocatalysts with various microstructures by combining the tailored self-assembly of the meso-tetra(p-hydroxyphenyl) porphine photosensitizer with the growth of titanium dioxide (TiO₂). The porphyrin photoabsorption antenna efficiently extended the absorption range of TiO₂ in the visible region, while anatase TiO₂ promoted the efficient electron–hole separation of porphyrin. The photo-induced electrons were transferred to the surface of the Pt co-catalyst for the generation of hydrogen via water splitting, and the hole was utilized for the decomposition of methyl orange dye. The hybrid structure showed greatly increased photocatalytic performance compared to the core@shell structure due to massive active sites and increased photo-generated electron output. This controlled assembly regulation provides a new approach for the fabrication of advanced, structure-dependent photocatalysts.

Reactive oxygen species (ROS) mediated tumor cell death is a powerful anticancer strategy. Cuproptosis is a copper-dependent and ROS-mediated prospective tumor therapy strategy. However, the complex tumor microenvironment (TME), low tumor specificity, poor therapy efficiency, and lack of imaging capability impair the therapy output of current cuproptosis drugs. Herein, we designed a dual-responsive two-dimensional metal-organic framework (2D MOF) nanotheranostic via a coordination self-assembly strategy using Au(III) tetra-(4-pyridyl) porphine (AuTPyP) as the ligand and copper ions (Cu²⁺) as nodes. The dual-stimulus combined with the protonation of the pyridyl group in AuTPyP and deep-penetration ultrasound (US) together triggered the controlled release in an acidic TME. The ultrathin structure (3.0 nm) of nanotheranostics promoted the release process. The released Cu²⁺ was reduced to Cu⁺ by depleting the overexpressed glutathione (GSH) in the tumor, which not only activated the Ferredoxin 1 (FDX1)-mediated cuproptosis but also catalyzed the overexpressed hydrogen peroxide (H₂O₂) in the tumor into reactive oxygen species via Fenton-like reaction. Simultaneously, the released AuTPyP could specifically bind with thioredoxin reductase and activate the redox imbalance of tumor cells. These together selectively induced significant mitochondrial vacuoles and prominent tumor cell death but did not damage the normal cells. The fluorescence and magnetic resonance imaging (MRI) results verified this nanotheranostic could target the HeLa tumor to greatly promote the self-enhanced effect of chemotherapy/cuproptosis and tumor inhibition efficiency. The work helped to elucidate the controlled assembly of multiresponsive nanotheranostics and the high-specificity ROS regulation for application in anticancer therapy.

Currently used drugs for glioblastoma (GBM) treatments are ineffective, primarily due to the significant challenges posed by strong drug resistance, poor blood-brain barrier (BBB) permeability, and the lack of tumor specificity. Here, we report two cationic fluorescent anticancer agents (TriPEX-ClO4 and TriPEX-PF6) capable of BBB penetration for efficient GBM therapy via paraptosis and ferroptosis induction. These aggregation-induced emission (AIE)-active agents specifically target mitochondria, effectively triggering ATF4/JNK/Alix-regulated paraptosis and GPX4-mediated ferroptosis. Specifically, they rapidly induce substantial cytoplasmic vacuolation, accompanied by reactive oxygen species generation and intracellular Ca2+ overload, thereby disrupting metabolisms and inducing non-apoptotic cell death. In vivo imaging revealed that TriPEX-ClO4 and TriPEX-PF6 successfully traversed the BBB to target orthotopic glioma and initiated effective synergistic therapy post-intravenous injection. Our AIE drugs emerged as the pioneering paraptosis inducers against drug-resistant GBM, significantly extending survival up to 40 days compared to temozolomide (20 days) in drug-resistant GBM-bearing mice. These compelling results open up new venues for the development of fluorescent anticancer drugs and innovative treatments for brain diseases.

Toxic amyloid-beta (Aβ) plaque and harmful inflammation are two leading symptoms of Alzheimer’s disease (AD). However, precise AD therapy is unrealizable due to the lack of dual-targeting therapy function, poor BBB penetration, and low imaging sensitivity. Here, we design a near-infrared-II aggregation-induced emission (AIE) nanotheranostic for precise AD therapy. The anti-quenching emission at 1350 nm accurately monitors the in vivo BBB penetration and specifically binding of nanotheranostic with plaques. Triggered by reactive oxygen species (ROS), two encapsulated therapeutic-type AIE molecules are controllably released to activate a self-enhanced therapy program. One specifically inhibits the Aβ fibrils formation, degrades Aβ fibrils, and prevents the reaggregation via multi-competitive interactions that are verified by computational analysis, which further alleviates the inflammation. Another effectively scavenges ROS and inflammation to remodel the cerebral redox balance and enhances the therapy effect, together reversing the neurotoxicity and achieving effective behavioral and cognitive improvements in the female AD mice model.