In vivo CAR-T therapy is shifting cell engineering from ex vivo manufacturing to direct programming of endogenous immune cells. Viral-vector platforms have advanced rapidly, particularly in oncology, where durable CAR expression and long-term immune surveillance may match disease biology. Nanocarrier-mediated in vivo CAR-T represents a mechanistically distinct strategy. Rather than serving as a transient substitute for viral-vector CAR-T, it may offer a separate therapeutic logic based on reversible CAR expression, repeatable dosing, modular payload design and tunable immune activation. These features are especially relevant for diseases in which a limited period of engineered T-cell activity can produce durable biological effects, such as B-cell-driven autoimmune disease, inflammatory disorders and tissue remodeling. This Opinion discusses the design principles that may define the next phase of nanocarrier-mediated in vivo CAR-T. Indication selection depends on whether transient and repeatable T-cell engineering offers a clear advantage over existing biologics. Productive delivery requires evaluation beyond bulk lymphoid-organ accumulation, with emphasis on microanatomical niches and defined T-cell subsets. CAR expression kinetics should be matched to disease-specific therapeutic windows, balancing efficacy with reversibility and safety. Nanocarrier immunogenicity and repeat-dose pharmacology also require control to avoid nonspecific inflammation, altered biodistribution and inconsistent T-cell programming. More broadly, in vivo CAR-T can serve as an entry point for transient and modular programming of disease-relevant immune-cell functions. Defining this framework will be essential for translating nanocarrier-based cell engineering from proof of delivery to controllable immune therapy.
Lipid nanoparticle (LNP) screening has rapidly expanded in scale through pooled barcoding and related high-throughput approaches. However, current screening paradigms remain largely centred on biodistribution, bulk tissue accumulation and mRNA-based reporter readouts, which do not necessarily capture the biological events that determine therapeutic activity in vivo. In this Opinion, we highlight three major limitations of current LNP screening: the disconnect between particle-associated signals and functional delivery, the influence of cellular and physiological context on apparent LNP performance, and the limited transferability of mRNA-based rankings across therapeutic payloads. We propose that future screening frameworks should move towards function-centric, context-resolved and cargo-aware evaluation, linking formulation identity more directly to the intended biological action of the delivered payload.
Metallic nanoparticles (MNPs) have found broad biomedical applications owing to their unique physicochemical and physiological properties. A large number of MNPs are designed to function inside the body as diagnostics or therapeutics. In recent years, there has been a growing research interest on the in vivo biotransformation and metabolism of nanoparticles in order to fully understand their life cycles within the body. In this review, we summarized recent breakthroughs in unraveling the in vivo biotransformation and metabolic processes of different MNPs, and discussed how these processes might relate to the transport, clearance and toxicity of MNPs in vivo, as well as how the physicochemical properties of MNPs impact their in vivo biotransformation profiles. In addition, we also discussed leveraging the biotransformation process of MNPs for biomedical applications and useful strategies to regulate their in vivo biotransformation efficiency. In the end, we summarized current methods for studying the biotransformation of MNPs and proposed perspectives as well as key questions that remain to be answered in the future. A clear understanding of the nanoparticle biotransformation process not only advances the basic science of physiology and toxicology in the nano-regime, but also provides important guidance for the development of related nanomedicines.
Radiotheranostics integrating diagnostic and therapeutic radionuclides into a single targeted platform is pivotal to precision oncology. For decades, clinical radiopharmaceutical development has been dominated by the covalent “bifunctional chelator + targeting vector” paradigm. While this framework has enabled numerous clinical translations, it faces inherent bottlenecks: difficulties in chelating large-radius radionuclides, restricted multimodal integration capacity, off-target radiation toxicity, and limited blood-brain barrier delivery efficiency. In a recent comprehensive review in Nature Reviews Chemistry, Moreno-Alcántar et al. systematically elaborate that supramolecular self-assembly systems, including metallacages, interlocked rotaxanes, and in situ self-assembly, provide a modular, stimuli-responsive toolset to address these limitations, which offer new avenues for innovating in vivo radiopharmaceutical delivery [1]. Building on this work, we discuss key advances in this field, analyze the potential translational challenges, and highlight priority directions for future research.
Artificial nanozymes avoid the intrinsic fragility of natural enzymes, offering excellent environmental robustness and tunable catalytic activities for precision nanomedicine. However, the catalytic performance of nanozymes is determined by multidimensional physicochemical parameters, including size, morphology, composition, and facet exposure. Traditional trial-and-error approaches struggle to effectively navigate the vast chemical space, leaving complex structure-activity relationships largely obscured. To overcome this barrier, machine learning (ML) is rapidly transforming nanozyme engineering from empirically-driven exploration into a predictive, data-centric science. This review systematically summarizes the latest progress in the closed-loop design of therapeutic nanozymes via ML. Rather than just listing algorithms for practical ML, we systematically demonstrated how data-driven workflows accelerate high-throughput virtual screening. Crucially, we highlight the essential role of explainable ML (e.g., SHAP analysis) in interpreting the algorithmic black box to reveal the underlying physicochemical mechanisms governing catalysis. Bridging computation and clinical application, we also comprehensively examine the deployment of AI-tailored nanozymes in precision therapy, including tumor management, inflammatory microenvironment remodeling, tissue regeneration, and intelligent in vitro diagnostics. Finally, by addressing potential challenges, such as data standardization and the in vitro-to-in vivo translational gap, we constructed a strategic outline toward autonomous, intelligent, and personalized catalytic medicine.
Cu-based electrocatalysts with Cu0/Cu+ interfaces are promising for renewable-powered electrosynthesis, but suffer from Cu+ reduction under reductive conditions, resulting in catalyst deactivation. Herein, we propose an electron‑withdrawing and active-hydrogen‑trapping dual-barrier strategy on a well-designed CuRu aerogel to protect the Cu+ sites from over-reduction, yielding a stable and continuous highly active surface and thus overcoming the conventional activity–stability trade‑off. In-/ex-situ characterizations and calculations confirm that within the CuRu aerogel, Ru sites manipulate both electronic structure and active hydrogen pathways to create an electron- and active-hydrogen-deficient state on Cu sites, thus stabilizing Cu+ sites. These Cu+ sites anchor NOx to form NO, and Ru sites mediate active hydrogen to accelerate the subsequent rate‑determining N–O bond cleavage, while the continuous aerogel network affords a seamless and stable pathway for mass transfer, ensuring a stable and efficient NO3–-to-NH3 conversion. The optimized Cu1Ru1 aerogel achieves a remarkable ammonia yield rate of 3.2 ± 0.22 mmol cm−2 h-1 and a high Faradaic efficiency of 99.4% at −0.1 V (vs. RHE), and sustains over 360 hours of continuous operation at an industrially relevant current density. Our work introduces a novel mediator-induced stabilization strategy, advancing both catalyst design and fundamental understanding of active-phase maintenance in electrocatalysis.
Cancer nanomedicines have improved the pharmacological performance of anticancer agents, yet their efficacy in solid tumors remains constrained by inadequate intratumoral transport and insufficiently selective payload release within dense tumor tissues. Herein, we report a nanoconfined biomineralization strategy that enables ultrasmall albumin nanocages for tumor-penetrating drug delivery and tumor-associated cathepsin B-activated therapy. With irinotecan used as a clinically relevant model payload, albumin confines the formation of irinotecan-based ionic nanocomplexes within its cavity, generating size-controllable ultrasmall nanocages. These nanocages show enhanced cellular uptake, prolonged circulation and increased tumor accumulation, and undergo accelerated irinotecan release in acidic, cathepsin B-rich lysosomal environments through proteolytic disruption of the albumin shell, thereby strengthening antitumor efficacy with reduced intestinal and hematological toxicity. Their ultrasmall architecture further promotes intratumoral distribution, modulates stromal barriers, and facilitates the subsequent delivery of macromolecular or nanoparticulate therapeutics, including anti-PD-L1 antibody and albumin-bound paclitaxel. In pancreatic and colorectal tumor models, this strategy potentiates irinotecan-based chemotherapy, clinically relevant combination regimens and immune checkpoint blockade. These findings establish nanoconfined biomineralization of albumin nanocages as an effective approach to integrate tumor penetration and tumor-associated enzyme-activated drug release for solid-tumor therapy.
Chronic osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) poses substantial therapeutic challenges due to a self-perpetuating cycle of bacterial colonization protected by devitalized bone fragments. Conventional antibiotics poorly reconcile pathogen eradication with bone restoration. Purine biosynthesis plays a central role in almost all organisms, yet the bacterial-specific enzymatic machinery provides a potential target for selective eradication with minimal adverse effects on healthy tissues. In this study, we developed multifunctional chlorogenic acid (CGA)-strontium nanoparticles (CGA@Sr) that integrate selective eradication of MRSA through purine metabolism interference with bone regeneration. Transcriptomic analysis confirmed that CGA@Sr interfere with critical metabolic processes, particularly purine metabolism, and disrupt MRSA surface transport systems and quorum sensing, thereby enabling effective bacterial clearance over 90%. It is noteworthy that, the CGA@Sr significantly down-regulated the bacterial-specific enzymes PurK and PurE (with expression of mRNA decreasing by 39.8% and 49.1% in the CGA@Sr group) within the de novo purine biosynthesis process, thereby enabling localized, selective MRSA eradication while exhibiting negligible cytotoxicity to normal tissues. Meanwhile, the sustained release of Sr2+ promotes the osteogenic differentiation of BMSCs and supports subsequent bone tissue regeneration (49.08% BV/TV at day 28). Overall, this work offers novel insights into the management of the complex pathophysiological environment associated with MRSA-infected chronic osteomyelitis.
Molecular semiconductors are attractive spin transport media because of their intrinsically weak spin relaxation. However, in laterally continuous films typically regarded as bulk transport media, spin-polarized carriers propagate through spatially unconfined pathways, limiting the room-temperature spin transport efficiency to ∼5% and constituting a long-standing bottleneck in molecular spintronics. Here, we introduce spatial confinement as a new structural-design strategy, in which molecular semiconductors are engineered into laterally separated transport channels to suppress spin relaxation and enable efficient spin transport. This strategy is implemented through controlled phase separation to form aligned nanocolumn-shaped channels, which are subsequently integrated into molecular spin valves using an electrode-transfer technique. The resulting devices exhibit a room-temperature spin transport efficiency of up to 16.1%, surpassing all previously reported values for molecular semiconductor-based spin valves. This record performance originates from a more than fortyfold reduction in effective spin relaxation strength. Moreover, the devices exhibit excellent environmental and operational stability, retaining more than 90% of their initial spin transport efficiency after 120 days of ambient storage or 8000 operating cycles under a bias of 10 mV. The spatial-confinement strategy is broadly extendable to other spintronic material systems and establishes a general structural-design paradigm for achieving highly efficient room-temperature spin transport, thereby providing a reliable device foundation for advanced spintronic functionalities such as spin logic and spin-based information processing.
Conventional cancer vaccines are constrained by tumor antigen heterogeneity and inadequate dendritic cells (DCs) activation. Herein, we proposed a morphology-guided physical immunoconduction strategy employing needle-like shaped nano-hydroxyapatite (N-nHA) as a multifunctional platform that orchestrated a coordinated lysis-capture-delivery-presentation-activation cascade. The N-nHA morphology selectively induces tumor lytic cell death, liberating a highly heterogeneous library of endogenous tumor antigens (>4622 species), including clinically relevant targets like melanoma-associated antigen-E1 (MAGE-E1) and damage-associated molecular patterns (DAMPs). Exposed (100) crystal facets of N-nHA, enriched with Ca2 + coordination sites, faciliated in situ capture and stabilization of these disordered components, forming immunogenic antigen-DAMP complexes and enabling standardized, high-fidelity antigen processing. N-nHA’s elongated morphology enhanced lymph node trafficking (4.5-fold enrichment), establishing a sustained-release antigen reservoir that ensured spatiotemporal antigen-DCs colocalization within lymphoid tissues. Furthermore, N-nHA exhibited intrinsic adjuvant properties, potently augmenting DCs uptake, antigen processing, cross-presentation, and maturation. This drove robust T-cell responses and increased CD8⁺ tumor-infiltrating lymphocyte infiltration. In the B16F0 murine melanoma model, this platform achieved a 98.5% tumor growth inhibition rate. Hence, this work established the physical immunoconductor leveraging intrinsic material properties, including morphology and crystallographic facets, to reprogram endogenous antigen presentation, laying a new foundation for broadly applicable, exogenous-free personalized cancer vaccines.
Plant-derived nano-formulations offer promising new approaches to enhance the therapeutic efficacy of cancer vaccines and T cells-based immunotherapy. These immunomodulatory formulations can stimulate the dendritic cells or γδ T cells to evoke the antitumor immunity, showing brilliant potentials in clinic translations.
With the global rise in cancer incidence, the development of effective and safe therapeutic strategies remains an urgent priority. Although radiotherapy (RT) is widely used in clinical oncology, its therapeutic efficacy is often compromised by the hypoxic tumor microenvironment, which induces radioresistance. Therefore, alleviating tumor hypoxia to enhance radiosensitivity has emerged as a promising strategy for improving radiotherapeutic outcomes. Herein, we developed bovine serum albumin (BSA)-modified PdPt nanosheets (PdPt@BSA) with intrinsic catalytic activity, radiosensitizing capability, and photothermal properties for enhanced cancer therapy. PdPt@BSA effectively amplified X-ray-induced cellular damage, as evidenced by increased reactive oxygen species (ROS) generation, aggravated mitochondrial dysfunction, and enhanced DNA double-strand breaks. Notably, PdPt@BSA alleviated tumor hypoxia through catalytic oxygen generation, accompanied by the downregulation of hypoxia-inducible factor-1α (HIF-1α), thereby overcoming hypoxia-induced radioresistance and significantly enhancing the therapeutic efficacy of radiotherapy. In addition, PdPt@BSA exhibited strong near-infrared absorption and outstanding photothermal conversion efficiency, which further potentiated tumor radiosensitization under near-infrared irradiation. In vivo studies demonstrated that PdPt@BSA-based combination therapy markedly suppressed tumor growth with minimal systemic toxicity. Moreover, PdPt@BSA partially induced immunogenic cell death, suggesting their potential to activate antitumor immune responses. Overall, this work presents a PdPt nanosheet-based nanoplatform that integrates catalytic hypoxia modulation, radiosensitization, and photothermal enhancement, providing a promising strategy for improving cancer radiotherapy.
Molecular ultrasound imaging with targeted microbubbles offers the opportunity for non-invasive assessment of disease-specific biomarkers and therefore opens the scope for real-time diagnosis and precise therapy monitoring. However, despite extensive preclinical research, clinical translation remains very limited. Here, we describe our efforts to complete the required regulatory steps before initiating clinical evaluation of integrin-targeted poly(butyl cyanoacrylate) microbubbles (IMB). In this context, we established a comprehensive translational pipeline addressing manufacturing, methodological, and regulatory challenges. First, we implemented a Good Manufacturing Practice-compatible manufacturing process, including lyophilization and sterilization, and defined standardized analytical assays for ligand quantification, acoustic performance, and molecular binding. We proved that IMB retained their physicochemical and functional properties after lyophilization, γ-sterilization, and 12-month storage, enabling suitability for clinical logistics and distribution. In regulatory aligned safety studies, we obtained a good tolerability profile with no evidence of genotoxicity or acute toxicity up to 33-fold of the expected human dose. After intravenous injection, the IMB were predominantly cleared by the mononuclear phagocyte system, with a blood half-life of 4 min. By using a clinical ultrasound system in tumor-bearing mice, we finally demonstrated specific microbubble binding to αvβ3-integrin-expressing tumor vessels and the generation of 3.5-fold enhanced ultrasound signals compared to nontargeted microbubbles. By linking GMP manufacturing, standardized quality control, and regulatory-aligned safety evaluation, this study demonstrates that IMB meet the key translational requirements and thus clears the path to progress to the first clinical trials evaluating molecular ultrasound with targeted polymeric microbubbles in integrin-associated diseases like neoplasia or inflammatory disorders.
The increasing interest in nanocarbon materials as metal-free catalysts has sparked claims of their sustainability and efficiency in organic synthesis. However, these claims often lack critical comparison with conventional catalytic methods. In this study, we present a systematic evaluation of nanocarbon catalysts, including graphene oxide, fullerene derivatives, and carbon quantum dots, and their use in representative C–C and C–N bond-forming reactions. Each nanocatalyzed transformation is directly compared with a well-established traditional protocol, considering yields and selectivity, as well as green chemistry factors such as reaction conditions, energy input, solvent use, and the presence or absence of metals. This approach allows for an evidence-based assessment of whether the application of nanocarbon catalysts provides genuine environmental and practical advantages. In several cases, nanomaterials deliver measurable improvements; in others, traditional protocols remain superior in terms of sustainability and efficiency. Our findings highlight the need for a more critical, data-driven perspective on the adoption of nanocatalysts and contribute to a balanced understanding of their role in modern green chemistry.
