A DNA origami device spatially controls CD95 signalling to induce immune tolerance in rheumatoid arthritis.

DNA origami is capable of spatially organizing molecules into sophisticated geometric patterns with nanometric precision. Here we describe a reconfigurable, two-dimensional DNA origami with geometrically patterned CD95 ligands that regulates immune cell signalling to alleviate rheumatoid arthritis. In response to pH changes, the device reversibly transforms from a closed to an open configuration, displaying a hexagonal pattern of CD95 ligands with ~10 nm intermolecular spacing, precisely mirroring the spatial arrangement of CD95 receptor clusters on the surface of immune cells. In a collagen-induced arthritis mouse model, DNA origami elicits robust and selective activation of CD95 death-inducing signalling in activated immune cells located in inflamed synovial tissues. Such localized immune tolerance ameliorates joint damage with no noticeable side effects. This device allows for the precise spatial control of cellular signalling, expanding our understanding of ligand-receptor interactions and is a promising platform for the development of pharmacological interventions targeting these interactions.

Photoactivated Formation of an Extravascular Dynamic Hydrogel as an Intelligent Blood Flow Regulator to Reprogram the Immunogenic Landscape.

Long-term tumor starvation may be a potential strategy to elevate the antitumor immune response by depriving nutrients. However, combining long-term starvation therapy with immunotherapy often yields limited efficacy due to the blockage of immune cell migration pathways. Herein, an intelligent blood flow regulator (BFR) is first established through photoactivated in situ formation of the extravascular dynamic hydrogel to compress blood vessels, which can induce long-term tumor starvation to elicit metabolic stress in tumor cells without affecting immune cell migration pathways. By leveraging methacrylate-modified nanophotosensitizers (HMMAN) and biodegradable gelatin methacrylate (GelMA), the developed extravascular hydrogel dynamically regulates blood flow via enzymatic degradation. Additionally, aPD-L1 loaded into HMMAN continuously blocks immune checkpoints. Systematic in vivo experiments demonstrate that the combination of immune checkpoint blockade (ICB) and BFR-induced metabolic stress (BIMS) significantly delays the progression of Lewis lung and breast cancers by reshaping the tumor immunogenic landscape and enhancing antitumor immune responses.

Custom-Design of Multi-Stimuli-Responsive Degradable Silica Nanoparticles for Advanced Cancer-Specific Chemotherapy.

Chemotherapy is crucial in oncology for combating malignant tumors but often encounters obatacles such as severe adverse effects, drug resistance, and biocompatibility issues. The advantages of degradable silica nanoparticles in tumor diagnosis and treatment lie in their ability to target drug delivery, minimizing toxicity to normal tissues while enhancing therapeutic efficacy. Moreover, their responsiveness to both endogenous and exogenous stimuli opens up new possibilities for integrating multiple treatment modalities. This review scrutinizes the burgeoning utility of degradable silica nanoparticles in combination with chemotherapy and other treatment modalities. Commencing the elucidation of degradable silica synthesis and degradation mechanisms, emphasis is placed on the responsiveness of these materials to endogenous (e.g., pH, redox reactions, hypoxia, and enzymes) and exogenous stimuli (e.g., light and high-intensity focused ultrasound). Moreover, this exploration delves into strategies harnessing degradable silica nanoparticles in chemotherapy alone, coupled with radiotherapy, photothermal therapy, photodynamic therapy, gas therapy, immunotherapy, starvation therapy, and chemodynamic therapy, elucidating multimodal synergies. Concluding with an assessment of advances, challenges, and constraints in oncology, despite hurdles, future investigations are anticipated to augment the role of degradable silica in cancer therapy. These insights can serve as a compass for devising more efficacious combined tumor treatment strategies.

Ferroptosis Detection: From Approaches to Applications.

Understanding the intricate molecular machinery that governs ferroptosis and leveraging this accumulating knowledge could facilitate disease prevention, diagnosis, treatment, and prognosis. Emerging approaches for the in situ detection of the major regulators and biological events across cellular, tissue, and in living subjects provide a multiscale perspective for studying ferroptosis. Furthermore, advanced applications that integrate ferroptosis detection and the latest technologies hold tremendous promise in ferroptosis research. In this review, we first briefly summarize the mechanisms and key regulators underlying ferroptosis. Ferroptosis detection approaches are then presented to delineate their design, mechanisms of action, and applications. Special interest is placed on advanced ferroptosis applications that integrate multifunctional platforms. Finally, we discuss the prospects and challenges of ferroptosis detection approaches and applications, with the aim of providing a roadmap for the theranostic development of a broad range of ferroptosis-related diseases.

Delivery of triptolide: a combination of traditional Chinese medicine and nanomedicine.

As a natural product with various biological activities, triptolide (TP) has been reported in anti-inflammatory, anti-tumor and anti-autoimmune studies. However, the narrow therapeutic window, poor water solubility, and fast metabolism limit its wide clinical application. To reduce its adverse effects and enhance its efficacy, research and design of targeted drug delivery systems (TDDS) based on nanomaterials is one of the most viable strategies at present. This review summarizes the reports and studies of TDDS combined with TP in recent years, including passive and active targeting of drug delivery systems, and specific delivery system strategies such as polymeric micelles, solid lipid nanoparticles, liposomes, and stimulus-responsive polymer nanoparticles. The reviewed literature presented herein indicates that TDDS is a multifunctional and efficient method for the delivery of TP. In addition, the advantages and disadvantages of TDDS are sorted out, aiming to provide reference for the combination of traditional Chinese medicine and advanced nano drug delivery systems (NDDS) in the future.

Coordinating the Mechanisms of Action of Ferroptosis and the Photothermal Effect for Cancer Theranostics.

Combination therapy based on different mechanisms of cell death has shown promise in tumor therapy. However, when different modalities are integrated, the maximum synergy of the therapeutic effects is often lacking in the design. Herein, we report a cancer theranostic nanomedicine formula developed by considering the mechanisms of action of ferroptosis and the photothermal effect in combination therapy. The croconaine molecule was encapsulated as both a photothermal converter and an iron-chelating agent with BSA, thus leading to biocompatible and stable Cro-Fe@BSA nanoparticles (NPs). The Cro-Fe@BSA NPs in the tumor milieu showed an activated photothermal effect leading to enhanced radical formation owing to the temperature-dependent Fenton reaction kinetics, while radical formation during ferroptosis in turn prevented the heat-induced formation of heat shock proteins and thus the self-protection mechanism of cancer cells in response to heat. The activatable photoacoustic and magnetic resonance imaging performance of the Cro-Fe@BSA NPs also enabled safe and reliable cancer theranostics.

Recent developments in mesoporous polydopamine-derived nanoplatforms for cancer theranostics.

Polydopamine (PDA), which is derived from marine mussels, has excellent potential in early diagnosis of diseases and targeted drug delivery owing to its good biocompatibility, biodegradability, and photothermal conversion. However, when used as a solid nanoparticle, the application of traditional PDA is restricted because of the low drug-loading and encapsulation efficiencies of hydrophobic drugs. Nevertheless, the emergence of mesoporous materials broaden our horizon. Mesoporous polydopamine (MPDA) has the characteristics of a porous structure, simple preparation process, low cost, high specific surface area, high light-to-heat conversion efficiency, and excellent biocompatibility, and therefore has gained considerable interest. This review provides an overview of the preparation methods and the latest applications of MPDA-based nanodrug delivery systems (chemotherapy combined with radiotherapy, photothermal therapy combined with chemotherapy, photothermal therapy combined with immunotherapy, photothermal therapy combined with photodynamic/chemodynamic therapy, and cancer theranostics). This review is expected to shed light on the multi-strategy antitumor therapy applications of MPDA-based nanodrug delivery systems.

Solvent-Assisted Self-Assembly of a Metal-Organic Framework Based Biocatalyst for Cascade Reaction Driven Photodynamic Therapy.

Biocatalytic reactions in living cells involve complex transformations in the spatially confined microenvironments. Inspired by biological transformation processes, we demonstrate effective biocatalytic cascade driven photodynamic therapy in tumor-bearing mice by the integration of an artificial enzyme (ultrasmall Au nanoparticles) with upconversion nanoparticles (NaYF4@NaYb0.92F4:Er0.08@NaYF4)zirconium/iron porphyrin metal-organic framework core-shell nanoparticles (UMOF NPs) which act as biocatalysts and nanoreactors. The construction of core-shell UMOF NPs are realized by using a unique "solvent-assisted self-assembly" method. The integration of ultrasmall AuNPs on the UMOFs matrix leads to glucose depletion, providing Au-mediated cancer therapy via glucose oxidase like catalytic activity. Meanwhile, the UMOF matrix acts as a near-infrared (NIR) light photon-activated singlet oxygen generator through a continuous supply of oxygen via hydrogen peroxide decomposition upon irradiation. Such kinds of biocatalysts offer exciting opportunities for biomedical, catalytical ,and energy applications.

An Albumin-Binding T1- T2 Dual-Modal MRI Contrast Agents for Improved Sensitivity and Accuracy in Tumor Imaging.

Magnetic resonance imaging (MRI) diagnosis is better assisted by contrast agents that can augment the signal contrast in the imaging appearance. However, this technique is still limited by the inherently low sensitivity on the recorded signal changes in conventional T1 or T2 MRI in a qualitative manner. Here, we provide a new paradigm of MRI diagnosis using T1- T2 dual-modal MRI contrast agents for contrast-enhanced postimaging computations on T1 and T2 relaxation changes. An albumin-binding molecule (i.e., truncated Evans blue) chelated with paramagnetic manganese ion was developed as a novel T1- T2 dual-modal MRI contrast agent at high magnetic field (7 T). Furthermore, the postimaging computations on T1- T2 dual-modal MRI led to greatly enhanced signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) in both subcutaneous and orthotopic brain tumor models compared with traditional MRI methods. The T1- T2 dual-modal MRI computations have great potential to eliminate suspicious artifacts and false-positive signals in mouse brain imaging. This study may open new avenues for contrast-enhanced MRI diagnosis and holds great promise for precision medicine.

Improving the Theranostic Potential of Exendin 4 by Reducing the Renal Radioactivity through Brush Border Membrane Enzyme-Mediated Degradation.

As highly expressed in insulinomas, the glucagon-like peptide-1 receptor (GLP-1R) is believed to be an attractive target for diagnosis, localization, and treatment with radiolabeled exendin 4. However, the high and persistent radioactivity accumulation of exendin 4 in the kidneys limits accurate diagnosis and safe, as well as effective, radiotherapy in insulinomas. In this study, we intend to reduce the renal accumulation of radiolabeled exendin 4 through degradation mediated by brush border membrane enzymes. A new exendin 4 ligand NOTA-MVK-Cys40-Leu14-Exendin 4 containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator was synthesized and labeled with 68Ga. The in vitro mouse serum stability and cell binding affinity of the tracer were evaluated. Initial in vitro cleavage of the linker was determined by incubation of a model compound Boc-MVK-Dde with brush border membrane vesicles (BBMVs) with and without the inhibitor of neutral endopeptidase (NEP). Further cleavage studies were performed with the full structure of NOTA-MVK-Cys40-Leu14-Exendin 4. Kidney and urine samples were collected in the in vivo metabolism study after intravenous injection of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4. The microPET images were acquired in INS-1 tumor model at different time points; the radioactivity uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 in tumor and kidneys were determined and compared with the control radiotracer without MVK linker. 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was stable in mouse serum. The MVK modification did not affect the affinity of NOTA-MVK-Cys40-Leu14-Exendin 4 toward GLP-1R. The in vitro cleavage study and in vivo metabolism study confirmed that the MVK sequence can be recognized by BBM enzymes and cleaved at the amide bond between Met and Val, thus releasing the small fragment containing Met. MicroPET images showed that the tumor uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was comparable to that of the control, while the kidney uptake was significantly reduced. As a result, more favorable tumor to kidney ratios were achieved. In this study, a novel exendin 4 analogue, NOTA-MVK-Cys40-Leu14-Exendin 4, was successfully synthesized and labeled with 68Ga. With the cleavable MVK sequence, this ligand could be cleaved by the enzymes on kidneys, and releasing the fragment of 68Ga-NOTA-Met-OH, which will rapidly excrete from urine. As the high and consistent renal radioactivity accumulation could be significantly reduced, NOTA-MVK-Cys40-Leu14-Exendin 4 shows great potential in the diagnosis and radiotherapy for insulinoma.

Novel curcumin analogue 14p protects against myocardial ischemia reperfusion injury through Nrf2-activating anti-oxidative activity.

BACKGROUND: Alleviating the oxidant stress associated with myocardial ischemia reperfusion has been demonstrated as a potential therapeutic approach to limit ischemia reperfusion (I/R)-induced cardiac damage. Curcumin, a natural compound with anti-oxidative activity, exerts beneficial effect against cardiac I/R injury, but poor chemical and metabolic stability. Previously, we have designed and synthesized a series of mono-carbonyl analogues of curcumin (MACs) with high stability. This study aims to find new anti-oxidant MACs and to demonstrate their effects and mechanisms against I/R-induced heart injury. METHODS: H9c2 cells challenged with H2O2 or TBHP were used for in vitro bio-screening and mechanistic studies. The MDA, H2O2 and SOD levels in H9C2 cells were determined, and the cell viability was assessed by MTT assay. Myocardial I/R mouse models administrated with or without the compound were used for in vivo studies. RESULTS: The in vitro cell-based screening showed that curcumin analogues 8d and 14p exhibited strong anti-oxidative effects. Pre-treatment of H9c2 cells with 14p activated Nrf2 signaling pathway, attenuated H2O2-increased MDA and SOD level, followed by the inhibition of TBHP-induced cell death and Bax/Bcl-2-caspase-3 pathway activation. Silencing Nrf2 significantly reversed the protective effects of 14p. In in vivo animal model of myocardial I/R, administration of low dose 14p (10mg/kg) reduced infarct size and myocardial apoptosis to the same extent as the high dose curcumin (100mg/kg). CONCLUSION: These data support the novel curcumin analogue 14p as a promising antioxidant to decrease oxidative stress and limit myocardial ischemia reperfusion injury via activating Nrf2.

Injectable conductive hydrogel remodeling microenvironment and mimicking neuroelectric signal transmission after spinal cord injury.

Severe spinal cord injury (SCI) leads to dysregulated neuroinflammation and cell apoptosis, resulting in axonal die-back and the loss of neuroelectric signal transmission. While biocompatible hydrogels are commonly used in SCI repair, they lack the capacity to support neuroelectric transmission. To overcome this limitation, we developed an injectable silk fibroin/ionic liquid (SFMA@IL) conductive hydrogel to assist neuroelectric signal transmission after SCI in this study. The hydrogel can form rapidly in situ under ultraviolet (UV) light. The mechanical supporting and neuro-regenerating properties are provided by silk fibroin (SF), while the conductive capability is provided by the designed ionic liquid (IL). SFMA@IL showed attractive features for SCI repair, such as anti-swelling, conductivity, and injectability. In vivo, SFMA@IL hydrogel used in rats with complete transection injuries was found to remodel the microenvironment, reduce inflammation, and facilitate neuro-fiber outgrowth. The hydrogel also led to a notable decrease in cell apoptosis and the achievement of scar-free wound healing, which saved 45.6 ± 10.8 % of spinal cord tissue in SFMA@IL grafting. Electrophysiological studies in rats with complete transection SCI confirmed SFMA@IL's ability to support sensory neuroelectric transmission, providing strong evidence for its signal transmission function. These findings provide new insights for the development of effective SCI treatments.

Neutrophil Targeting Platform Reduces Neutrophil Extracellular Traps for Improved Traumatic Brain Injury and Stroke Theranostics.

Traumatic brain injuries (TBI) and stroke are major causes of morbidity and mortality in both developing and developed countries. The complex and heterogeneous pathophysiology of TBI and cerebral ischemia-reperfusion injury (CIRI), in addition to the blood-brain barrier (BBB) resistance, is a major barrier to the advancement of diagnostics and therapeutics. Clinical data showed that the severity of TBI and stroke is positively correlated with the number of neutrophils in peripheral blood and brain injury sites. Furthermore, neutrophil extracellular traps (NETs) released by neutrophils correlate with worse TBI and stroke outcomes by impairing revascularization and vascular remodeling. Therefore, targeting neutrophils to deliver NETs inhibitors to brain injury sites and reduce the formation of NETs can be an optimal strategy for TBI and stroke therapy. Herein, the study designs and synthesizes a reactive oxygen species (ROS)-responsive neutrophil-targeting delivery system loaded with peptidyl arginine deiminase 4 (PAD4) inhibitor, GSK484, to prevent the formation of NETs in brain injury sites, which significantly inhibited neuroinflammation and improved neurological deficits, and improved the survival rate of TBI and CIRI. This strategy may provide a groundwork for the development of targeted theranostics of TBI and stroke.

Bioactivable STING Nanoagonists to Synergize NIR-II Mild Photothermal Therapy Primed Robust and Long-Term Anticancer Immunity.

Pharmacological activation of the stimulator of interferon genes (STING) pathway has become a promising strategy for cancer immunotherapy. However, the insufficient tumorous accumulation, rapid clearance, and short duration of drug efficacy in the tumor microenvironment of small structural STING agonists greatly compromise the therapeutic efficacy. Herein, a tumorous extracellular matrix (ECM) is presented anchoring STING agonist-based photoimmunothernostic nanomedicine (SAPTN) that can be activated by mild-temperature photothermal therapy (mild PTT) induced neutrophilic inflammation. The SAPTN owns second window near-infrared (NIR-II) photonics properties fitting for NIR-II fluorescence and photoacoustic imaging-guided cancer therapy. The aggregates SAPTN targeting to the ECM provide slow and continuous release of potent STING agonists diABZIs. The mild PTT and long-lasting STING agonists released in the ECM synergistically prime systematic, robust, and long-term anticancer immunity. In a tumor model, this approach leads to complete tumor eradication in about 100% of mice with orthotopic breast tumors, and the mice regained tumor-free survival of at least 2 months. In addition, the immune-mediated abscopal effect shows inhibition of the distant solid tumor growth by intratumoral administration of SAPTN with laser irradiation. Overall, this approach represents a generalized photoactivable nanomedicine to prime anticancer immunity for improved cancer theranostics.

Recent advances of bioresponsive polymeric nanomedicine for cancer therapy.

A bioresponsive polymeric nanocarrier for drug delivery is able to alter its physical and physicochemical properties in response to a variety of biological signals and pathological changes, and can exert its therapeutic efficacy within a confined space. These nanosystems can optimize the biodistribution and subcellular location of therapeutics by exploiting the differences in biochemical properties between tumors and normal tissues. Moreover, bioresponsive polymer-based nanosystems could be rationally designed as precision therapeutic platforms by optimizing the combination of responsive elements and therapeutic components according to the patient-specific disease type and stage. In this review, recent advances in smart bioresponsive polymeric nanosystems for cancer chemotherapy and immunotherapy will be summarized. We mainly discuss three categories, including acidity-sensitive, redox-responsive, and enzyme-triggered polymeric nanosystems. The important issues regarding clinical translation such as reproducibility, manufacture, and probable toxicity, are also commented.

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer.

Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of human cancers. FGFR2 is frequently amplified or mutated in cancers; therefore, it is an attractive target for tumor therapy. Despite the development of several pan-FGFR inhibitors, their long-term therapeutic efficacy is hindered by acquired mutations and low isoform selectivity. Herein, we report the discovery of an efficient and selective FGFR2 proteolysis-targeting chimeric molecule, LC-MB12, that incorporates an essential rigid linker. LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2 among the four FGFR isoforms; this may promote greater clinical benefits. LC-MB12 exhibits superior potency in FGFR signaling suppression and anti-proliferative activity compared to the parental inhibitor. Furthermore, LC-MB12 is orally bioavailable and shows significant antitumor effects in FGFR2-dependent gastric cancer in vivo. Taken together, LC-MB12 is a candidate FGFR2 degrader for alternative FGFR2-targeting strategies and offers a promising starting point for drug development.

Ligustrazine Nanoparticle Hitchhiking on Neutrophils for Enhanced Therapy of Cerebral Ischemia-Reperfusion Injury.

Ischemic stroke is a refractory disease that endangers human health and safety owing to cerebral ischemia. Brain ischemia induces a series of inflammatory reactions. Neutrophils migrate from the circulatory system to the site of cerebral ischemia and accumulate in large numbers at the site of inflammation across the blood-brain barrier. Therefore, hitchhiking on neutrophils to deliver drugs to ischemic brain sites could be an optimal strategy. Since the surface of neutrophils has a formyl peptide receptor (FPR), this work modifies a nanoplatform surface by the peptide cinnamyl-F-(D)L-F-(D)L-F (CFLFLF), which can specifically bind to the FPR receptor. After intravenous injection, the fabricated nanoparticles effectively adhered to the surface of neutrophils in peripheral blood mediated by FPR, thereby hitchhiking with neutrophils to achieve higher accumulation at the inflammatory site of cerebral ischemia. In addition, the nanoparticle shell is composed of a polymer with reactive oxygen species (ROS)-responsive bond breaking and is encased in ligustrazine, a natural product with neuroprotective properties. In conclusion, the strategy of hitching the delivered drugs to neutrophils in this study could improve drug enrichment in the brain, thereby providing a general delivery platform for ischemic stroke or other inflammation-related diseases.

Ethyl 7-methyl-2-((1-methyl-1H-pyrrol-2-yl)methyl-ene)-3-oxo-5-phenyl-3,5-dihydro-2H-thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate.

In the structure of the title compound, C(22)H(21)N(3)O(3)S, the thia-zole ring forms dihedral angles of 88.83 (7) and 9.39 (9)°, respectively, with the benzene and pyrrole rings. The dihydro-pyrimidine ring adopts a flattened boat conformation. The olefinic double bond is in a Z conformation.

Hesperetin ameliorates glioblastoma by inhibiting proliferation, inducing apoptosis, and suppressing metastasis.

Background: Glioblastoma is the most common type of malignant tumor of the brain. Despite substantial improvements in therapy, the 5-year survival rate of patients with glioblastoma remains low. Antitumor drug development has encountered considerable obstacles, which can be attributed to metastasis and the blood-brain barrier (BBB). Hesperetin (HSP), derived from citrus fruits, exhibits several biological properties, including anticancer and anti-inflammatory activities. In addition, in vitro models have shown that HSP can easily cross the BBB. The purpose of the present study was to explore the effects and underlying mechanisms of HSP on glioblastoma cells. Methods: GL261 cell were cultured and treated with different dose HSP. The cell viability was assessed with Cell Counting Kit-8 (CCK-8) assay. The cell apoptosis was determined using an Annexin V/propidine iodide (PI) staining and Hoechst staining and detection assay, cell migration and invasion were observed on GL261 cells using Matrigel-coated Transwells and Wound-Healing assay. The expression of proteins was detected by Western blotting. Results: HSP suppressed cell proliferation and could induce apoptosis, the latter of which might be regulated through the Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor-kappa B (NF-κB) pathways. Furthermore, HSP inhibited cell migration and invasion by downregulating the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, and inhibited epithelial-mesenchymal transition (EMT) by upregulating the expression of E-cadherin while downregulating N-cadherin and vimentin expression. Conclusions: These findings suggest HSP to be an alternative preventive and therapeutic antiglioblastoma drug that may be especially useful for patients with recurrent glioblastoma.

Smart NIR-II croconaine dye-peptide for enhanced photo-sonotheranostics of hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality rates. The development of novel nanomaterials represents an important direction for precise HCC theranostics. The combination of photothermal and sonodynamic therapy has provided great benefits for HCC therapy. Theranostic agents in the second near-infrared window (NIR-II, 1000-1700 nm) show great prospects because of their extraordinarily high detection sensitivity, resolution, and deep penetration. Methods: A sharp pH-sensitive self-assembling Glypican-3 (GPC3)-binding peptide (GBP) dye, CR-PEG-GBP, was developed as an intelligent nanoprobe for NIR-II imaging and photoacoustic (PA) imaging-guided photothermal therapy (PTT) and sonodynamic therapy (SDT) of HCC. Results: This small molecule assembled nanoprobe exhibited advantageous properties, such as responding to a decrease in pH (from normal tissue (pH 7.4) to the tumor microenvironment (pH ~6.5)) and aggregating - from small nanoprobes (<20 nm at pH 7.4) - into large nanoparticles (>160 nm at pH 6.5 and >510 nm at pH 5.5) that enables enhanced imaging and therapeutic effects. Because CR-PEG-GBP can self-aggregate in situ in an acidic tumor microenvironment, it shows high tumor accumulation and long tumor retention time, while being excretable from normal tissues and safe. Conclusions: This intelligent self-assembling small molecule strategy provides a simple yet efficient solution for HCC theranostics and may open up new avenues for designing clinically translatable probes for HCC treatment.