Yijin Liu

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.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, and acute exacerbations drive most of its burden. Around half of exacerbations are infection related, and penicillin-class antibiotics are widely used. However, penicillin allergy labels, often inaccurate, may divert prescribing towards broader-spectrum agents and worsen outcomes. We therefore examined whether such labels are associated with antibiotic prescribing patterns and subsequent risk of COPD exacerbations in a large cohort. Methods: We conducted a retrospective cohort study in the Kunshan Aging Research with E-health (KARE) database (2016– 2024). We included 14,900 patients with COPD aged ≥ 40 years. Exposure was a documented penicillin allergy label in the electronic medical record. Outcomes were the risk and rate of subsequent COPD exacerbations. Cox proportional hazards models estimated the association with time to first exacerbation, and negative binomial regression assessed exacerbation rates. Results: Of 14,900 patients, 722 (4.8%) had a penicillin allergy label. Overall, 2018 (13.5%) experienced at least one exacerbation during a median follow-up of 4.1 years. Compared with unlabeled patients, those with a penicillin allergy label received more broad-spectrum antibiotics and had a higher risk of exacerbations (adjusted hazard ratio 1.39, 95% confidence interval 1.17– 1.65) and higher exacerbation rates (adjusted incidence rate ratio 1.56, 95% confidence interval 1.25– 1.93). Conclusion: In this Chinese COPD cohort, penicillin allergy labels were associated with broader-spectrum antibiotic use and an increased burden of exacerbations. Systematic verification and de-labelling of penicillin allergy may help optimise antibiotic use and improve COPD outcomes.

Checkpoint blockade therapies targeting PD‐L1 have revolutionized cancer immunotherapy, yet their efficacy is constrained by systemic immune toxicity and inadequate immune infiltration in certain tumor types. Here, we introduce a synergistic gene‐silencing nanosystem based on a target‐selective Pistol ribozyme (PS473) encapsulated within a manganese‐based, pH‐responsive metal–organic framework (NKMOF‐101‐[Mn]). The engineered PS473 exhibited high cleavage efficiency toward GU‐rich PD‐L1 mRNA motifs and was further activated by Mn ^{2 +} cofactors. NKMOF‐101‐[Mn] not only protects the ribozyme from nuclease degradation but also enables localized Mn ^{2 +} release to increase catalytic activity and innate immune signaling under the acidic tumor microenvironment. In vitro, PS473@NKMOF‐101‐[Mn] markedly suppressed PD‐L1 expression and promoted macrophage activation. In the B16F10 melanoma model, this system achieved over 90% tumor inhibition, enhanced immune cell infiltration and activation, and exhibited minimal systemic toxicity. Transcriptomic profiling further revealed the upregulation of immune‐related pathways, supporting a synergistic mechanism of gene silencing and immune activation. Overall, this study established a ribozyme‐directed immunotherapeutic platform with strong potential for precision cancer therapy via checkpoint modulation and immune reprogramming.

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.

RNA-based medicines have transformed modern therapeutics, exemplified by the clinical success of small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and mRNA vaccines. Small self-cleaving ribozymes – compact catalytic RNA species capable of programmable cleavage and ligation – were among the earliest RNA drugs explored, yet their progress was initially hindered by instability, nuclease degradation, inefficient intracellular delivery, and immune activation. In this Perspective, we discuss how recent technological convergence has revived their potential. Comparative genomics has uncovered new catalytic classes, including Twister, Pistol, Hatchet, and Hovlinc ribozymes, thereby expanding the catalytic repertoire. High-resolution structural and computational studies have elucidated their reaction architectures, while chemical modifications and advanced nanocarrier systems – such as DNA nanostructures, spherical nucleic acids, and lipid nanoparticles – have markedly improved molecular stability and delivery efficiency. Emerging applications, from ligand-responsive aptazymes and ribozyme-SNA conjugates to the StitchR RNA trans-ligation platform, further illustrate the expanding biomedical versatility of catalytic RNA. Together, these advances are redefining the role of ribozymes in oncology, virology, and genetic medicine. No longer a dormant concept, ribozymes now stand as an evolving frontier – rationally engineered catalysts that continue to inspire technological creativity and renewed optimism in RNA therapeutics.

The emergence of bacterial infections as a critical public health challenge underscores the urgent need for innovative therapeutic strategies. We designed and synthesized a series of novel heteroaryl bishydrozono nitroimidazoles and their analogs by strategically hybridizing multiple molecular components through diverse linkers. Among the newly synthesized compounds, compound 4 displayed a broad-spectrum antibacterial profile with low cytotoxicity and hemolysis. It could inhibit the proliferation of methicillin-resistant Staphylococcus aureus and reduce its metabolic activity with low bacterial resistance. Further investigations revealed that the highly active compound 4 could not only disrupt cell membrane integrity and induce excessive reactive oxygen species within bacterial membranes, but also intercalate into DNA to form a supramolecular 4-DNA gyrase complex and cause cell death. These results demonstrated that compound 4 should have large potential as a promising candidate in the ongoing battle against resistant bacterial infections.

Uridine (rU) and 2'-deoxyuridine (dU) are common DNA lesions. dU is repaired through a base excision repair (BER) pathway initiated by uracil DNA glycosylase (UDG), while rU is typically removed from DNA via ribonucleotide excision repair, mediated by RNase H2. In this study, we report that rU is also repaired through the UDG-mediated BER pathway. We found that UDG catalyzes the removal of uracil from rU embedded in DNA, but exhibits no activity toward rU in RNA. Biochemical and crystallographic analyses revealed that the 2'-OH group of rU is effectively accommodated by UDG and directly participates in catalyzing the hydrolysis of the N-glycosidic bond. The abasic site product generated upon removal of uracil from rU by UDG is further processed by downstream BER enzymes to restore undamaged DNA. Our findings suggest that UDG-initiated BER constitutes a previously unrecognized pathway for the repair of rU-specific ribonucleotides. Additionally, we developed a method for selectively quantifying rU content in DNA. Using this method, we determined that rU repair by UDG is not a major pathway in human cells. This discovery expands our understanding of the diverse biological functions of UDG, and inspires further investigation to determine the role of its rU-removal in cells.

Gene-targeted therapies are revolutionizing cancer treatment due to their high specificity and low toxicity. Among these, ribozymes hold promise as independent gene therapy agents capable of directly cleaving target mRNAs. The pistol ribozyme, discovered in 2015, stands out for its compact structure and robust cleavage activity, making it a promising candidate for RNA silencing under physiological conditions. However, its clinical application is limited by nuclease susceptibility and biological barrier penetration. To overcome these obstacles, this study presents an innovative gene-regulation strategy incorporating engineered pistol ribozymes into a spherical nucleic acid (SNA) nanocarrier. This catalytic SNA nanocarrier, built on a DNA core-shell framework, combines the ribozyme with doxorubicin (Dox) to form the ApRz-CS/Dox nanoplatform. The design of ApRz-CS/Dox features a homopolymerized DNA core and a reticular DNA shell, enhancing stability. Tumor-targeting aptamers are arranged on its surface, directing it specifically to cancer cells. Within the target cells, the ribozyme is released in response to overexpressed miR-21, facilitating the cleavage of polo-like kinase 1 mRNA. This integrated approach effectively combines gene therapy with the chemotherapeutic effects of Dox, addressing the challenges associated with the delivery of newly developed nucleic acid drugs and offering a promising strategy for enhanced cancer treatment.