Central nervous system (CNS) disorders-including ischemic stroke, traumatic brain/spinal cord injury, Parkinson's disease, and Alzheimer's disease-have long faced limitations in achieving functional recovery and disease-modifying therapies because of their complex pathophysiological mechanisms. Traditional therapies are often constrained by poor penetration across CNS barriers, limited participation in multiple pathological cascades, and insufficient persistence of therapeutic effects. Nanozymes are a class of nanomaterials with enzyme-like catalytic activity and tunable physicochemical properties. Not only do these nanozymes continuously scavenge reactive oxygen and nitrogen species in pathological environments through stable multi-enzyme synergistic effects by leveraging their abundant active sites, but also serve as multimodal therapeutic delivery platforms to achieve efficient drug delivery, opening up new avenues for neuroprotection and regenerative medicine. This review systematically examines the fundamental characteristics, classification systems, and functional design approaches of nanozymes, along with their potential for combined therapeutic strategies, including synergistic applications with drugs, hydrogels, genes, or cells. Additionally, it summarizes the latest advancements in neuroprotection and repair associated with CNS disorders. The review further analyzes current limitations and challenges related to clinical translation and offers insights into future research directions to enhance scientific knowledge and clinical applications in this significant field.
Glioblastoma (GBM) is highly aggressive and difficult to treat, partly due to the lack of in vitro models that faithfully recapitulate its biochemical and mechanobiological microenvironment. Synthetic hydrogels lack tumor-specific cues, while animal-derived dECM suffers from batch variability, limiting standardization. Methods:Here, we describe a GBM-derived dECM bioink formulated through mechanically stimulated 3D GBM culture within GelMA/HAMA hydrogels. By controlling the matrix stiffness to match GBM tissue and applying various compressive stresses that mimic intracranial solid stress, we identified a mechanobiological activation range that maximized secretion of GBM-associated factors, including GDF15, MMP2, and MMP9. Results:The resulting bioink exhibited upregulated tumor-specific biochemical signals compared to hydrogel-only controls. Micromesh-bioprinted GBM constructs fabricated from this bioink demonstrated enhanced proliferation, invasion-related gene expression, and ECM remodeling. Co-culture with endothelial cells or fibroblasts further reconstructed stromal activation, paracrine signaling, and matrix dynamics associated with GBM progression and therapeutic resistance. Conclusion:This strategy establishes a reproducible, bioactive GBM-specific bioink platform for physiologically relevant 3D GBM modeling and GBM-on-chip applications.
Background:Pathological ocular neovascularization is a major driver of vision-threatening retinal diseases. This study aimed to investigate the role and therapeutic potential of miR-15a-5p in ocular neovascular disorders. Methods:miR-15a-5p expression levels were assessed in intraocular fluids from patients with ocular neovascular diseases. Functional assays were performed in retinal endothelial cells under pathological conditions to evaluate proliferation and endothelial-to-mesenchymal transition. In vivo, miR-15a-5p was delivered via intravitreal injection in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) mouse models. Therapeutic effects on pathological neovascularization were analyzed and compared with anti-VEGF treatment, including assessments of retinal structural integrity, retinal function, gliosis, and fibrotic changes. miR-15a-5p-knockout mice were used to examine retinal vascular developmental abnormalities and enhanced neovascular responses following miR-15a-5p deficiency. Safety evaluations of systemic and ocular administration were performed in both healthy and neovascularized mice. Mechanistic studies investigated whether miR-15a-5p directly targeted VEGF and Smad2. Results:miR-15a-5p was significantly upregulated in intraocular fluids from patients with ocular neovascular diseases. Overexpression of miR-15a-5p inhibited retinal endothelial cell proliferation and endothelial-to-mesenchymal transition in vitro. In OIR and CNV models, miR-15a-5p treatment reduced retinal neovascularization, decreased reactive gliosis, and maintained retinal thickness and electrophysiological function. In miR-15a-5p-knockout mice, loss of miR-15a-5p impaired normal retinal vascular development. Mechanistically, miR-15a-5p directly targeted VEGF and Smad2, modulating angiogenic and fibrotic pathways. Compared with anti-VEGF therapy, miR-15a-5p demonstrated stronger anti-fibrotic and neuroprotective effects without affecting postnatal development or systemic metabolism. No ocular or systemic toxicity was observed at therapeutic doses. Conclusions:miR-15a-5p regulates angiogenesis and fibrosis by targeting VEGF and Smad2. These findings suggest that miR-15a-5p is a promising therapeutic candidate for the treatment of ocular neovascular diseases.
Rationale:The preservation of the tumor immune microenvironment (TIME) ex vivo is essential for investigating tumor-immune interactions and developing effective immunotherapies. However, current culture models often fail to maintain autologous immune cells or support high-throughput testing. To overcome these limitations, we establish and validate a novel miniaturized-tumor culture (MTC) platform. Methods:To build the MTC platform, we took tumor tissues from both mouse models and human patients. We processed these tissues into 100-500 μm fragments. Supplementation with IL-2 and IL-7 in culture maintained long-term intra-tumoral T cell survival. We then evaluated whether the platform could maintain autologous lymphoid populations and respond to immune checkpoint blockade (ICB), through co-culture assays with peripheral blood mononuclear cells (PBMCs) or splenocytes. The system accurately recapitulates drug response and resistance in both immunocompetent and immunodeficient models. Finally, we screened a high-throughput drug library to identify agents that re-sensitize tumors to anti-PD-L1 therapy. To figure out the underlying mechanisms, we used bulk RNA-sequencing, flow cytometry, and targeted CXCL13 antibody neutralization. Results:The MTC platform demonstrated better preservation of autologous lymphoid populations and remained responsive to ICB. Co-culture assays revealed enhanced immune cell infiltration upon ICB treatment. Furthermore, the MTC models recapitulated drug response and resistance phenotypes. Our screen identified axitinib (AXI) as the most potent agent for re-sensitizing tumors to anti-PD-L1 therapy across different cancer types. Mechanistically, AXI potentiates antigen presentation in tumor and dendritic cells. It also enhances cytotoxic T-cell function via the upregulation of CXCL13. Finally, CXCL13 blockade effectively abrogated AXI-induced T cell recruitment and tumor regression. Conclusions:The MTC platform serves as a high-fidelity, high-throughput tool for modeling the TIME. It provides a valuable framework for developing novel anti-cancer strategies and elucidating their underlying mechanisms of action.
Rationale:Since the therapeutic resistance of triple-negative breast cancer (TNBC) is mainly attributable to excessive glutathione (GSH) accumulation and its 'cold' immune landscape, we designed biomimetic CuZnS@BSA nanoregulators that exploit a pH-triggered 'disarm-and-attack' cascade, thereby initiating a well-defined, sequential therapeutic process in the acidic tumor microenvironment. Methods:Biomimetic CuZnS@BSA nanoclusters were synthesized via a self-assembly method. Their pH-responsive release kinetics and synergistic therapeutic mechanisms (GSH depletion, ROS generation, and cuproptosis) were systematically evaluated in vitro using 4T1 cells. In vivo anti-tumor efficacy, immune microenvironment remodeling, and anti-metastatic effects were investigated in subcutaneous and lung metastasis TNBC mouse models, both alone and in combination with PD-L1 blockade. Results:The platform first releases H2S to deplete intracellular GSH, thus removing the major antioxidant defenses of the tumor, then follows with the release of Cu2+ to induce cuproptosis, which effectively bypasses the apoptosis resistance commonly seen in TNBC. In addition, the released Zn2+ acts as an immune modulator by promoting the recognition of leaked mitochondrial DNA. This activates the cGAS-STING signaling pathway, and in vivo experiments clearly showed that it remodels the tumor microenvironment in a highly favorable manner, characterized by increased CD8+ T cell infiltration and enhanced dendritic cell maturation. Conclusion:Combining this nanoregulator with PD-L1 blockade led to potent suppression of both subcutaneous tumor growth and lung metastasis, thus providing a direct, elegant link between metabolic reprogramming and systemic immune activation for TNBC therapy.
Rationale:Acute kidney injury (AKI) is a life-threatening clinical syndrome characterized by high mortality, in which tubular epithelial cell death represents a key pathological event. Emerging evidence underscores the importance of the ubiquitin system in the progression of AKI. Here, we focus on the function of YOD1 in AKI. Methods:We generated tubular epithelial cells (TECs)-specific Yod1 knockout mice (YOD1CKO) by crossing Yod1fl/fl mice and Ggt1-cre mice. Both YOD1CKO mice and Yod1fl/fl littermates were subjected to cisplatin- or ischemia/reperfusion (I/R)-induced AKI models. Through co-immunoprecipitation (Co-IP) combined with LC-MS/MS analysis, we identified potential substrate proteins of YOD1. Results:We observed that YOD1 is predominantly expressed in TECs and is upregulated during AKI injury. Renal tubular specific Yod1 knockout significantly alleviated tubular damage and apoptosis in AKI mice. Mechanistically, we identified the pro-apoptotic protein Bax as a direct substrate of YOD1. YOD1 removes K63-linked ubiquitin chains from Bax at lysine 128 via its catalytic cysteine residue C155, thereby promoting Bax activation, and mitochondrial translocation and subsequent apoptosis. YOD1 failed to promote apoptosis in Bax-deficient cells, confirming Bax as the essential downstream mediator. Conclusions:Our study reveals a previously unrecognized YOD1-Bax regulatory axis that drives tubular apoptosis in AKI, and highlights YOD1 may hold therapeutic potential.
Magnetic hyperthermia (MH) has evolved from a localized thermal modality into an emerging intracellular immunomodulatory technology for cancer treatment. By employing magnetic nanoparticles (MNPs) to convert alternating magnetic fields into confined intracellular heat, MH enables precise spatial and temporal regulation of cellular stress responses while maintaining favorable biocompatibility and tumor selectivity. This review highlights recent advances that reposition MH as a cell-level immune regulation strategy, focusing on three interconnected aspects: (i) rational design of MNPs to optimize magnetic-to-thermal conversion efficiency and achieve precise intracellular heat transduction; (ii) integration of magnetic field-controlled MH with drug delivery and nano-heating modalities to enable synergistic intracellular regulation; and (iii) mechanistic insights into MH-induced immune modulation, including immunogenic cell death, immune cell activation, and its integration with tumor vaccines and cancer immunotherapy. Collectively, these advances establish MH as a versatile intracellular immunoregulatory platform and underscore its potential for precision cancer immunotherapy.
Bone marrow organ is characterized as a dynamic tissue with a complex microenvironment wherein hematopoietic stem cell (HSC) homeostasis is maintained, and the generation of various hematopoietic cell subsets is regulated. Organoids technology has been applied as an alternative tool for modeling complex tissue microenvironments in a laboratory setting through the self-organization of cells. Recent studies have established a platform capable of studying complex cellular interactions by generating bone marrow organoids (BMOs) from iPSCs. Moreover, BMOs can emulate the architecture observed of the bone marrow, including the various cell types, containing vascular-like networks, HSCs, mesenchymal stromal cells (MSCs), and mature hematopoietic cells. This review aimed to summarize how BMOs can provide foundational data essential for understanding similarities in the microenvironment and the pathological mechanisms underlying bone marrow diseases, as well as for developing new treatments. Furthermore, BMO systems represent a cutting-edge platform for studying hematopoiesis, disease mechanisms, and therapeutic screening, highlighting the recent trend toward physiologically relevant organoid-based models in regenerative and hematopoietic research.
Rationale: Trophoblast cell-surface antigen 2 (Trop2) is an essential therapeutic target in breast cancer, yet non-invasive methods for assessing its expression and predicting response to Trop2-directed antibody-drug conjugates (ADCs) remain limited. We aimed to evaluate the diagnostic accuracy of 68Ga-MY6349 positron emission tomography/computed tomography (PET/CT) in patients with breast cancer and assess its impact on clinical decision-making. Methods: We prospectively enrolled 73 patients with suspected or confirmed breast cancer who underwent both 68Ga-MY6349 and 18F-fluorodeoxyglucose (18F-FDG) PET/CT from December 2024 to April 2025. Lesion-based diagnostic performance was compared using histopathology and follow-up imaging as reference standards. Treatment decisions were recorded before and after 68Ga-MY6349 PET/CT. Serial 68Ga-MY6349 PET/CT was performed to assess the early metabolic response in three patients with triple-negative breast cancer receiving sacituzumab tirumotecan. Results: 68Ga-MY6349 PET/CT identified more malignant lesions (564 vs. 436) and fewer false positives (2 vs. 40) than 18F-FDG PET/CT. In the initial-staging cohort (n = 30), 68Ga-MY6349 PET/CT led to TNM stage upgrades in 6/30 patients (20%) and treatment modifications in 4/30. In the restaging cohort (n = 43), clinical management was altered in 5/43 patients (12%) owing to the identification of additional metastatic lesions or rectification of false-positive findings via 68Ga-MY6349 PET/CT. 68Ga-MY6349 PET/CT yielded higher overall tumor uptake (median maximum standardized uptake value (SUVmax), 5.9 vs. 4.1; P < 0.001) and improved lesion conspicuity, particularly in lymph node and metastatic lesions. Exploratory analysis in three patients receiving Trop2-ADC therapy showed that early changes in 68Ga-MY6349 uptake after two treatment cycles were concordant with the subsequent clinical response. Conclusions: 68Ga-MY6349 PET/CT demonstrated superior diagnostic performance to 18F-FDG PET/CT in breast cancer staging and diagnosis, directly influencing therapeutic strategies. Preliminary findings from the triple-negative breast cancer cases suggest that early changes in SUVmax may be associated with the treatment response to Trop2-targeted ADC therapy, warranting further prospective validation in larger patient populations.
Rationale:Doxorubicin (DOX) is a potent chemotherapeutic agent whose antitumor benefits are limited by a well-recognized, dose-dependent cardiotoxicity. While previous studies have implicated inflammatory pathways in DOX-induced cardiomyopathy (DIC), the role of CCR2 in this process remains incompletely defined. This study aims to investigate whether CCR2 deficiency confers cardioprotection against DIC and to uncover the molecular mechanisms involved. Methods:CCR2 knockout (CCR2⁻/⁻ ) mouse was subjected to both acute and chronic DIC models. Bone marrow transplantation was used to establish the functional contribution of CCR2-deficient macrophages. Autophagic flux was evaluated using complementary approaches, including a tandem mRFP-GFP-LC3 reporter, western blotting, immunofluorescence, and transmission electron microscopy. The mediator linking CCR2-deficient macrophages to cardiomyocytes was identified by proteomics and validated using recombinant IL12B protein and a neutralizing antibody. Results:CCR2 deficiency substantially improved cardiac function, as evidenced by preserved left ventricular ejection fraction, fractional shortening and reduced serum cardiac injury markers. Mechanistic studies revealed that CCR2⁻/⁻ hearts exhibited enhanced autophagic flux, with increased LC3B lipidation, autophagosome formation, and clearance of damaged cellular components. Proteomic profiling of cardiac macrophages identified interleukin-12B (IL12B) significantly upregulated in CCR2⁻/⁻ mouse. Recombinant IL12B protein administration activated cardiomyocyte autophagy through PI3K/Akt/mTOR pathway inhibition and reproduced the cardioprotective effects in WT mouse. Conversely, IL12B neutralization completely abolished CCR2 deficiency-mediated protection. Conclusions:Our findings identify a novel CCR2-IL12B-autophagy axis that critically regulates DOX-induced cardiotoxicity. CCR2 deficiency promotes IL12B secretion from cardiac macrophages, which directly activates protective autophagy in cardiomyocytes. These results establish CCR2 inhibition and IL12B supplementation as two promising therapeutic strategies to prevent chemotherapy-induced cardiomyopathy, providing a transformative approach to cardio-oncology.
The development of novel theranostic agents is a key initiative to address current limitations in disease diagnosis and therapy. Notably, targeting cyanine dyes (TCDs), by virtue of their excellent optical imaging performance, versatile structural modifiability, and multi-dimensional targeting specificity, facilitate the directional recognition of disease regions and exhibit tremendous application potential in theranostics. While a variety of TCDs have been successfully developed and their theranostic efficacy experimentally validated, researchers still lack a systematic summary of related studies. Although related advances in fluorescent probes, tumor theranostics, and NIR-II fluorophores have been reviewed, a focused and systematic overview of TCDs in terms of their synthesis, hierarchical targeting mechanisms, and multi-disease theranostic applications remains limited. Accordingly, this article systematically reviews TCDs' synthesis strategies, elucidates their "tissue-cell-organelle" hierarchical targeting mechanism, and summarizes the therapeutic applications in diseases including tumors, fibrotic diseases, metabolic diseases, and radiation-induced injuries. Compared with previous reviews, this review highlights the structure-inherent targeting properties of TCDs, their hierarchical targeting mechanisms, and their emerging theranostic potential beyond oncology. Meanwhile, this article outlines the core advantages and current challenges of TCDs in theranostic integration, and delineates key future directions, including precise and intelligent molecular design, photostability limitations, systematic preclinical evaluation, multimodal technology integration, and the expansion of disease application scenarios. It aims to provide comprehensive theoretical support for advancing the fundamental research and clinical translation of TCDs.
Rationale:Heart failure (HF) is increasingly recognized as a systemic disorder that extends beyond the heart and affects neurovascular tissues, including the retina. However, the mechanisms by which circulating factors from HF trigger retinal neuroinflammation remain unclear. Methods:HF was induced in adult mice by transverse aortic constriction (TAC). Retinal structure and function were evaluated using optical coherence tomography (OCT) and electroretinography (ERG). Parabiosis and plasma transfer experiments were performed to assess the role of circulating factors. Endothelial senescence, microglial activation, and inflammatory signaling were analyzed using immunofluorescence, qPCR, and molecular assays. The functional relevance of TGFβ2 and microglia was tested using anti-TGFβ2 antibody administration and microglial depletion with PLX5622 treatment. Results:TAC mice exhibited pronounced retinal thinning, diminished electroretinography (ERG) amplitudes, and reduced vascular density. Exposure of healthy mice to HF plasma reproduced these abnormalities, indicating that circulating mediators drive retinal injuries. TGFβ2 levels were markedly elevated in the plasma of both patients with HF and TAC mice. Mechanistically, TGFβ2 activated the pSMAD2/EP300 pathway in retinal endothelial cells, promoting H3K9 acetylation, P21 induction, and endothelial cell senescence. Senescent endothelial cells release proinflammatory factors that activate retinal microglia, leading to hypertrophic morphology, enhanced synaptic phagocytosis, and upregulation of cytokines such as IL1β, TNFα, and IL6. Neutralization of TGFβ2 or microglial depletion markedly reduced inflammation, preserved the retinal architecture, and restored visual function. Conclusions:Elevated TGFβ2 levels in heart failure drive retinal endothelial epigenetic senescence, which secondarily activates microglia and induces neuroinflammation. Endothelial-specific disruption of TGFβ2 signaling is sufficient to protect the retina independently of primary cardiac recovery. Targeting the TGFβ2-endothelial-microglia axis may represent a promising therapeutic strategy for preventing retinal neurovascular degeneration associated with systemic cardiac disease.
Rationale:Obesity and type 2 diabetes (T2D) are growing threats to human health, and their genetic basis is complex and not fully understood. Furthermore, the mitochondrial genome has been shown to encode for many microproteins that have a variety of biological effects. In this study we explore a newly discovered mitochondrial-derived microprotein (MDP) that may be responsible for some forms of diabetes in humans. Methods:We have performed a mitochondrial genome wide interaction study (MiWIS) and discovered a SNP that lies within the gene for an MDP and is associated with type 2 diabetes. We then used cell culture to confirm that this MDP has biological activity and used mass spectrometry to detect it. This novel MDP and more potent analogues were then administered in murine, in vivo studies in models of diabetes and obesity to determine the effects. Further analysis of the in vivo studies was performed with transcriptomic and proteomic techniques. Results:Our MiWIS found a SNP associated with type 2 diabetes in 3 independent cohorts that is found within a novel MDP that we have called MENTSH (MDP Encoded in the ND-Two Subunit of Humans). This common SNP is found in populations indigenous to the Americas that interrupts the start codon of MENTSH. Murine in vivo studies demonstrate that MENTSH administration improves insulin signaling, while analogues of MENTSH can potently block weight gain caused by a high fat diet. Mechanistically, our studies show that MENTSH activates AKT signaling in muscle, while reducing AKT signaling in fat. Conclusions:These observations highlight a new cause of metabolic dysfunction in a vulnerable population, suggesting that MENTSH could be an innovative, precision medicine approach to treating T2D.
Bacteria have emerged as promising living therapeutics for the treatment of infections, inflammatory disorders, metabolic diseases, and neoplastic diseases. However, their clinical efficacy is often compromised by in vivo barriers that reduce their viability and impair their function after administration. Rational engineering can help them sustain their viability under a harsh microenvironment and enhance their targetability as well as retention, ultimately improving their functional performance in vivo. This review starts with a concise synopsis of current status in live bacterial therapy, with particular emphasis on the major biological barriers to their in vivo application. Engineering strategies for harnessing bacterial intrinsic characteristics and overcoming their specific barriers are discussed. Representative examples are then presented to illustrate how engineered live bacteria overcome these biological barriers and achieve therapeutic applications via oral, topical, intravenous, and inhalational administration. Finally, we identify the key challenges associated with translating laboratory advances into reliable and safe clinical therapeutics.
The combination therapies are significantly more effective than monotherapies in enhancing anticancer efficacy, reducing drug-related toxicity, and lowering the risk of drug resistance in cancer treatment. However, achieving precise delivery of the drugs to the tumor site remains a major challenge. With the deepening exploration of surface-engineered nanocarriers, ligand-modified liposomal drug delivery systems (LLDDS) are constructed by integrating the active-targeting properties of functional ligands (such as peptides, glycans, and aptamers) with the inherent advantages of liposomes. LLDDS show promise for exhibiting strong tumor-targeting capability, improving pharmacokinetics, biodistribution, and therapeutic efficacy of anticancer agents, such as chemotherapy drugs, and enabling the multifunctional integration of multiple therapeutic strategies. This review summarizes the development of liposomes and ligand-mediated surface modification strategies. More significantly, the development of multifunctional liposomes, targeted delivery, improved anticancer effectiveness, and possible anticancer mechanisms are highlighted in the discussion of LLDDS's recent advancements for integrated therapy approaches in a variety of malignancies. Lastly, the potential and difficulties of clinical translation in this ever-evolving area are examined.
Rationale:Fusobacterium nucleatum (Fn) is associated with resistance to neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma (ESCC), but the underlying mechanism is unclear. We identified Fn-induced SPP1⁺ macrophages as key drivers of a cancer-associated fibroblast (CAF)-mediated spatial immune barrier that restricts CD8⁺ T-cell infiltration. Methods:Mannose-modified non-cationic thiourea lipid nanoparticles (NC-TNPM) were engineered to deliver Cas9 mRNA and SPP1-targeting sgRNA to macrophages. Their therapeutic efficacy was evaluated in Fn-associated ESCC models combined with chemotherapy and anti-PD-L1 treatment. Results:NC-TNPM achieved efficient SPP1 silencing, markedly reduced SPP1⁺ macrophages, disrupted the macrophage-CAF immune barrier, and restored intratumoral CD8⁺ T-cell infiltration. Combined with chemo-immunotherapy, NC-TNPM significantly suppressed tumor growth, enhanced cytotoxic T-cell activity, promoted macrophage repolarization, and showed no evident toxicity. Conclusions:Fn-induced SPP1⁺ macrophages drive immune exclusion and chemo-immunotherapy resistance in ESCC. Macrophage-targeted SPP1 editing with NC-TNPM overcomes this barrier and enhances therapeutic efficacy, highlighting a promising nanomedicine strategy for ESCC.
Carbonic anhydrase IX (CAIX) is an interesting therapeutic target in clear cell renal cell carcinoma (ccRCC), but gastrointestinal uptake impedes the clinical translation of CAIX-targeted radioligand. In this study, structure-guided optimization of a cyclic peptide scaffold was conducted to decouple tumor targeting from gastrointestinal retention. Methods:Five novel CAIX-targeting ligands were developed at the base of a cyclic peptide and evaluated in OS-RC-2 cell, small animal positron emission tomography/computed tomography (PET/CT), biodistribution, and radiotherapy experiments. The lead candidate was tested on 21 patients with cancer in comparison to 18F-FDG. Results:In preclinical experiments, ⁶⁸Ga/¹⁷⁷Lu-ZH2 exhibited sub-nanomolar CAIX affinity and a favorable pharmacokinetics, with preserved tumor uptake and markedly reduced gastrointestinal retention, compared with benchmark ⁶⁸Ga/¹⁷⁷Lu-DPI-4452. In mice, ¹⁷⁷Lu-ZH2 inhibited tumor growth and prolonged survival without evident toxicity. In a first-in-human study of 21 patients with renal masses, ⁶⁸Ga-ZH2 PET/CT was deemed safe and demonstrated a superior diagnostic performance to ¹⁸F-FDG, detecting additional primary tumors and metastases with higher contrast. Conclusions:These results establish 68Ga/177Lu-ZH2 as a CAIX-targeted imaging and potential therapeutic agent with favorable preclinical and early clinical imaging characteristics, enabling the sensitive detection of ccRCC and laying the groundwork for further therapeutic investigation.
