Jie Zhuang

Targeted clearance of pre-existing amyloid-β (Aβ) aggregation remains a central challenge in Alzheimer’s disease (AD) therapy. Here we report a computationally guided protein–gold hybrid nanostructure, _Aβ3FTn^Au, that integrates Aβ-recognition motifs into self-assembled human ferritin nanocages containing structurally defined gold nanoclusters composed of 12 gold atoms with Au–Au distances of 2.4–4.5 Å, enabling the selective recognition and disassembly of aggregated human Aβ. Structural analysis, mutagenesis and molecular simulations identify key interactions between gold-coordinating residues within _Aβ3FTn^Au (H118, T122, C130) and the Met35 residue of Aβ, revealing a mechanism in which multivalent engagement destabilizes fibrillar interfaces and promotes progressive plaque disassembly. In 5 × familial AD transgenic mice, systemic administration of _Aβ3FTn^Au reduced cerebral amyloid burden, preserved synaptic integrity and improved cognitive performance. This work establishes a rationally designed bioactive nanomaterial for targeted remodelling of pathological protein aggregates.

Mimicking endogenous immune cell responses holds great promise for repairing tissue damage in myocardial infarction (MI), yet challenges persist due to the heterogeneity, spatiotemporal dynamics, and diverse functions of macrophage subtypes during post-MI repair. Herein, we introduce a data-driven biomimetic strategy that leverages the sequential delivery of immune cell-mimicking nanoparticles to replicate the natural immune repair mechanisms. Using single-cell RNA sequencing, we analyzed the dynamic changes in immune cells during post-MI repair, revealing the distinct roles of macrophage subtypes in different stages of recovery. Building on these insights, we developed immune cell-mimicking nanoparticles and devised a sequential delivery strategy to emulate the temporal distribution of three macrophage subtypes (M2a, M2b, and M2c) throughout the MI repair process. Our results demonstrated that each macrophage subtype played a unique and time-dependent role in the repair process. Among various delivery strategies tested, the sequential delivery of M2a, M2b, and M2c nanoparticles emerged as the most effective approach for promoting MI recovery. This study not only provides an innovative framework for the design and application of immune cell-mimicking nanoparticles in MI treatment but also underscores the importance of replicating natural healing processes in nanomedicine development.

Low-permeability (LP) tumor vasculature constitutes a major barrier to efficient nanomedicine delivery, making quantitative assessment and mechanistic understanding of vascular permeability essential for the rational design of delivery strategies. Here, we introduce a deep learning-guided microneedle (MN) delivery platform that enables localized and spatiotemporally precise modulation of tumor vasculature to enhance nanoparticle extravasation. By integrating the MN system with an upgraded single-vessel analysis framework (nano-ISML 1.1), we quantitatively mapped vascular remodeling and nanoparticle transport across diverse tumor types and particle sizes. Localized histamine delivery via MNs selectively expanded endothelial junctions through VE-cadherin-mediated regulation, significantly increasing the frequency and length of interendothelial gaps, and thereby reprogramming LP tumors toward a high-permeability phenotype. This controlled vascular remodeling established a pronounced size-dependent permeability window, defined by locally induced gap dimensions that varied across tumor types, permitting efficient penetration of nanoparticles ≤200 nm while largely excluding particles >500 nm. By uniting nanotechnology, vascular biology, and artificial intelligence, this interdisciplinary framework provides a mechanistic and predictive paradigm for overcoming vascular barriers and advancing the rational design of tumor-targeted nanomedicines.

Cytotoxic T lymphocytes play a crucial role in anti-tumour immunity, with granzyme B (GrB) being a decisive factor in this process. Developing a GrB-based delivery system to mimic T cell-based immunotherapy holds promise but remains challenging. Here, we present an artificial metalloenzyme (nanozyme) with GrB-like protease activity capable of inducing caspase-dependent cell apoptosis. The nanozyme is based on the site-specific binding of Pd(II) ions to recombinant human heavy chain apo-ferritin nanocages to generate a binuclear catalytic centre consisting of two Pd atoms with bridging cysteine ligands, monodentate methionine and histidine residues, and two water molecules. We show that encapsulation of the Pd-ferritin complex within membrane-fused lipid nanoparticles comprising surface-displayed single-chain antibodies affords GrB-mimicking nanozyme-based nanovesicles capable of receptor-mediated delivery of the nanozyme into the cytoplasm of tumour cells and induction of caspase-dependent apoptosis. This study provides valuable insights into the construction of nano-delivery systems with artificial GrB activity and presents a promising therapeutic option for solid tumours.

Transferrin receptor 1 (TfR1), a widely expressed type II transmembrane glycoprotein located on the plasma membrane, is well known for its established role in cellular iron uptake. Nevertheless, emerging evidence implies that TfR1 exhibits previously unrecognized noncanonical functions. Herein, we demonstrated the nuclear translocation of TfR1 and revealed the interaction between TfR1 and p53 within the nucleus. Through comprehensive analyses at the proteomic, genomic, and transcriptomic levels, we demonstrated that this interaction significantly influences the transcriptional activity of p53 on its downstream target genes, which are highly enriched in DNA damage repair functions. Specifically, our investigation revealed the indispensable role of nuclear TfR1 in the regulation of the nucleotide excision repair (NER) pathway, exemplified by the transcriptional regulation of XPC. Notably, both in vitro and in vivo results revealed a positive regulatory role of TfR1 in the NER pathway. Subsequent phenomic analysis of clinical colorectal tumor samples confirmed a positive correlation between nuclear TfR1 levels and tumor malignancy, aggressive features, and metastasis. Collectively, our findings highlight the non-classical function of TfR1, emphasizing its importance in the regulation of gene expression, as well as tumor progression.

Nanozymes play a pivotal role in mitigating excessive oxidative stress, however, determining their specific enzyme-mimicking activities for intracellular free radical scavenging is challenging due to endo-lysosomal entrapment. In this study, we employ a genetic engineering strategy to generate ionizable ferritin nanocages (iFTn), enabling their escape from endo-lysosomes and entry into the cytoplasm. Specifically, ionizable repeated Histidine-Histidine-Glutamic acid (9H₂E) sequences are genetically incorporated into the outer surface of human heavy chain FTn, followed by the assembly of various chain-like nanostructures via a two-armed polyethylene glycol (PEG). Utilizing endosome-escaping ability, we design iFTn-based tetrameric cascade nanozymes with high superoxide dismutase- and catalase-mimicking activities. The in vivo protective effects of these ionizable cascade nanozymes against cardiac oxidative injury are demonstrated in female mouse models of cardiac ischemia-reperfusion (IR). RNA-sequencing analysis highlight the crucial role of these nanozymes in modulating superoxide anions-, hydrogen peroxide- and mitochondrial functions-relevant genes in IR injured cardiac tissue. These genetically engineered ionizable protein nanocarriers provide opportunities for developing ionizable drug delivery systems.

Designing dual-targeted nanomedicines to enhance tumor delivery efficacy is a complex challenge, largely due to the barrier posed by blood vessels during systemic delivery. Effective transport across endothelial cells is, therefore, a critical topic of study. Herein, we present a synthetic biology-based approach to engineer dual-targeted ferritin nanocages (Dt-FTn) for understanding receptor-mediated transport across tumor endothelial cells. By leveraging a genetically engineered logic-gated strategy, we coassembled various Dt-FTn in E. coli with tunable ratios of RGD-targeting and intrinsic TfR1-targeting ligands. These Dt-FTn constructs were employed to investigate the interaction between receptor-mediated vascular permeability and dual-targeted nanomedicines in low-permeability tumors. Through machine learning-based single vessel analysis, we uncovered the crucial role of dual-receptor expression profiles in determining the vascular transport of dual-targeted nanomedicines in tumors with low permeability. Using a patient-derived colon cancer model, we demonstrated a proof-of-concept that the optimal proportions of dual ligands in these nanomedicines can be customized based on tumor cell receptor expression profiles. This study provides valuable insights and guiding principles for the rational design of dual-targeted nanomedicines for tumor-targeted delivery.

The development of mitochondria-targeting nanozymes holds significant promise for treating myocardial ischemia-reperfusion (IR) injury but faces significant biological barriers. To overcome these obstacles, we herein utilized genetically engineered ferritin nanocages (i.e., imFTn) to develop mitochondria-targeting nanozymes consisting of three ferritin subunit assembly modules: an IR-injured cardiomyocyte-targeting module, a lysosome-escaping module, and a mitochondria-targeting module. Using imFTn as a nanozyme platform, we developed nanozymes capable of efficiently catalyzing the l-Arg substrate to produce NO. The imFTn-Ru exhibits NO-generating activities, reduces mitochondrial reactive oxygen species generation, inhibits mitochondrial permeability transition pore opening, and enhances mitochondrial membrane potential. Furthermore, imFTn-Ru provides synergistic effects by specifically targeting myocardial IR-injured tissues, facilitating their accumulation in mitochondria, and protecting mitochondria against myocardial IR-induced injury in both in vitro and in vivo models. This study underscores a rational approach to designing nanozymes for targeting specific subcellular organelles in the treatment of IR injury.