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Combating bacterial biofilm poses a significant challenge because of the dense extracellular polymeric substance (EPS) barrier and inherent drug tolerance. Herein, the designed core-shell nanoparticles (DA₃-NPs) that eradicate biofilm by precise in-situ phototherapy are reported. DA₃-NPs are self-assembled using thermosensitive azo-polymers (AP₃) to encapsulate GSH-degradable phototherapeutic polymers (DBP) via charge interaction. Notably, D-aminoalanine grafted onto the AP₃ serves as a critical component, providing an electroneutral shell and bacterial peptidoglycan targeting ability to the DA₃-NPs. Consequently, DA₃-NPs effectively penetrate EPS up to a depth of 60 µm and precisely target the bacteria within the biofilms. Upon exposure to laser irradiation and the GSH microenvironment, DA₃-NPs undergo sequential responses involving shell detachment and core disintegration. These processes facilitate point-to-point bacterial killing through the in-situ generations of ROS, carbon radicals and heat damage to the internal bacteria. Compared to non-targeted nanoparticles, DA₃-NPs exhibit a 61-fold increase in biofilm removal efficiency. This study thus presents a precise in-situ phototherapy strategy for nonantibiotic treatment of biofilm infections.

Natural polyphenols-mediated green photosterilization is promising but remains challenging in practical applications due to their unsatisfactory performance with insufficient intrinsic energy level and ROS generation. In this work, the molecular-level engineering strategy of natural polyphenols (quercetin, QC) by p-Methoxybezaldehyde (MB)-induced nucleophilic substitution is constructed for enhanced photodynamic MRSA therapy. Both the experimental and theoretical results disclose that the unprecedented H-aggregates of QC-MB supramolecular realized accelerated ISC with minimizing the energy level difference (ΔEst), achieving enhanced photodynamic performance with 2.2-fold enhancement on ¹O₂ quantum yield (75 %) compared to free quercetin (33 %). The well-designed photosensitizer realizes efficient MRSA elimination: with enhanced killing efficacy from 30.44 % to 99.95 % in vitro and effective eradication of mature biofilms. Mechanism study and gene transcription analysis reveal that the combined therapy of optical stimuli with QC-MB achieves the dual mechanism of ROS attack and virulence regulation against MRSA infection during the whole infection process. Moreover, the excellent biocompatibility and anti-infectious in vivo demonstrate the engineered QC-MB as a promising strategy for MRSA therapy.

Herein, crescent-shaped Janus nanoassemblies (Au-AIENPs) with high plasmonic and fluorescent activities are prepared by co-assembling oleylamine-coated gold nanoparticles (OA-AuNPs) and red-emitting aggregation-induced emission luminogens (AIEgens) in separate compartments of polymer nanoparticles. The obtained Au-AIENPs show typical Janus heterostructures, where AIEgens preferentially aggregate to form fluorescent core and OA-AuNPs are distributed in the polymer matrix to form a crescent-shaped plasmonic shell, thus resulting in effective spatial separation of OA-AuNPs and AIEgens to achieve the balance between plasmonic and fluorescent signals and reduce the mutual interference between signals. Taking advantage of the excellent plasmonic and fluorescent activities of Au-AIENPs, we successfully established a colorimetric and ratiometric fluorescence dual-mode lateral flow immunoassay (Au-AIENPs-RLFIA) for the visual and quantitative detection of aflatoxin B1 (AFB1) in corn sample. Under the developed conditions, the visual detection limit (vLOD) of the Au-AIENPs-RLFIA for colorimetric and ratiomentic fluorescence detection was 0.62 ng/mL and 0.02 ng/mL, respectively, while the quantitative LOD (qLOD) for ratiomentic fluorescence mode was as low as 0.0076 ng/mL. The above results indicate that the designed Janus Au-AIENPs are promising as dual-signal output probes and hold great potential for improving flexible dual-mode detection of various targets on the LFIA platform.

Brain arteriovenous malformations (BAVMs) are primarily associated with somatic activating pathogenic KRAS variants. KRAS-targeting therapy is emerging as a potential treatment for BAVMs. However, current molecular diagnosis relies on surgically obtained tissue samples. Here, we investigated the feasibility of using cell-free DNA (cfDNA) from the blood for molecular diagnosis in sporadic BAVM patients. We included 31 BAVM patients and extracted genomic DNA from BAVM tissues, while paired cfDNA was isolated from plasma. Additionally, fifty plasma cfDNA samples from unaffected individuals served as controls. By utilizing droplet digital polymerase chain reaction (ddPCR), we tested KRAS c.35 G>A p.Gly12Asp (p.G12D) and c.35 G>T p.Gly12Val (p.G12V) variants in all samples. Among the 31 BAVM samples, KRAS somatic mutations were identified in 24 patients (77 %), comprising 79 % (19 out of 24) p.G12D and 21 % (5 out of 24) p.G12V variants. The variant frequencies (VFs) ranged from 0.227 % to 8.327 %, with positive droplets ranging from 17 to 1025. 63 % (15 out of 24) of patients with KRAS mutations had≥2 positive droplets in their cfDNA samples. In contrast, in none of the 50 control samples more than two positive droplets were detected. Specifically, 13 plasma samples (68 %) were positive for p.G12D mutation. The VFs in plasma cfDNA samples ranged from 0.042 % to 5.172 %. Furthermore, ddPCR demonstrated a sensitivity of 63 %, specificity of 100 %, positive predictive value of 100 %, and negative predictive value of 81 % for detecting plasma cfDNA. The VFs in mutant tissues had an inverse trend with the largest nidus sizes, volumes, and patient age, while an opposite trend was observed in plasma cfDNA. Taken together, we successfully detected pathogenic somatic activating KRAS variants in cfDNA obtained from the plasma of BAVM patients. The diagnostic utility of liquid biopsy for BAVMs will facilitate the development of personalized therapeutic approaches and offer opportunities for novel strategies to halt, slow, or delay disease progression.

Optimal exposure and interaction of subunit antigens with the immune system are crucial for effective immunity. The epidermis and dermis, which harbor a significant population of antigen-presenting cells (APCs) and are broadly connected to the lymphatic system, serve as ideal sites for immunization to fulfill these objectives. However, the stratum corneum barrier severely hinders transdermal delivery of antigens. Here, we developed a transdermal platform integrating yeast-derived biomimetic glucan particles (GPs) and polymeric microneedles to overcome the hurdles and induce effective immunity. GPs served as carriers for encapsulating antigens in a pathogen-like manner. The antigen-loaded particles were concentrated within the tips of polymeric microneedle to solidify as tiny reservoirs, while the needle bodies were shaped using a fast-dissolving matrix. This tip-loaded approach enabled rapid administration for better compliance, followed by an extended antigen release at administration sites, aiming for recruiting more APCs. This microscale platform capacitated a multi-functional approach for subunit vaccine development by optimizing both delivery carriers and dosage forms with modulated release mechanisms to enhance antigen exposure and interaction, thereby promoting effective humoral and cellular immunity.

Modulating the inflammatory cerebral microenvironment via RNA interference holds great potentials for managing post-stroke ischemia-reperfusion (IR) injury. Herein, biomimetic nanocomplexes (NCs) cloaked with platelet-microglia hybrid membrane (HM) are developed to mediate microglia-targeted sphingosine kinase 1 siRNA (siSPHK-1) delivery against cerebral IR injury. The NCs consist of a cationic nano-core assembled from ROS-degradable, branched poly(β-amino ester) (BS) and siSPHK-1, and an outer shell of HM. After intravenous administration, the NCs accumulate at the lesion site due to platelet membrane (PM)-assisted microthrombus targeting, penetrate blood-brain barrier due to CD29-assisted transendothelial migration, and enter microglia via CD51/61-assisted homotypic targeting and CD29-assisted, receptor-mediated endocytosis. The over-produced ROS inside inflamed microglia triggers BS degradation and siSPHK-1 release, thereby provoking SPHK-1 silencing to remodel the inflammatory microenvironment, protect the neurovascular unit, and recover the cognitive/memory ability of IR-injured mice. This study reports a bio-inspired strategy to overcome the multiple physiological barriers against cerebral siRNA delivery, and renders promising implications for gene therapy against cerebral diseases.

Deep-seated osteomyelitis caused by bacterial infection, particularly methicillin-resistant Staphylococcus aureus (MRSA) infection, poses a significant challenge to treatment. In this study, we propose the utilization of a composite microwave (MW)-responsive polypyrrole-modified titanium carbide/zinc oxide (Ti₃C₂T_x/ZnO–PPy) heterostructure as a potential therapeutic option for MRSA-infected osteomyelitis. In vitro and in vivo experiments show that Ti₃C₂T_x/ZnO–PPy can effectively treat MRSA-induced osteomyelitis under MW irradiation, which is attributed to the enhanced in situ release of MW heat and reactive oxygen species (ROS). Density functional theory and MW network vector analysis further reveal that under MW irradiation, Ti₃C₂T_x/ZnO–PPy generates free electrons that move freely within the heterogeneous interface formed by Ti₃C₂T_x and ZnO, thereby enhancing the accumulation of charges. These charges combine with adsorbed oxygen at the interface to produce ROS. Furthermore, augmented dipole polarization induced by the functional groups on the surface of Ti₃C₂T_x and the interfacial polarization between Ti₃C₂T_x and ZnO contribute to good impedance matching and a favourable attenuation constant in the Ti₃C₂T_x/ZnO–PPy composite, resulting in superior MW thermal properties. Moreover, the polypyrrole-modified composite shows excellent biocompatibility. This efficient antimicrobial system with MW irradiation is expected to offer a viable approach to the management of osteomyelitis.

Cell heterogeneous nanomaterials based therapeutic strategies for Parkinson’s disease (PD) have been widely investigated, however, challenged by the potential toxicity, immunogenicity, limited drug loading efficiency, and restricted penetration through biological barriers. Herein, for the first time, a medicinal plant, Pueraria lobata derived exosomes (Pu-Exos) were demonstrated with excellent capability in overcoming cellular membrane and endosomal barriers, ensuring the efficient delivery of incorporated biomacromolecule cargos to SH-SY5Y cells. Upon that, Pu-Exos comprehensively improved the mitochondrial dysfunction of SH-SY5Y cells through removing dysfunctional mitochondria via PINK1-Parkin mediated mitophagy, and restoring ATP supplementation by preserving the activities of mitochondrial respiratory chain complexes I and V. Pu-Exos were then engineered with the ternary ligand, DSPE-PEG-RVG, forming Pu-Exos-PR that were further optimized for the cellular uptake and brain enrichment in vivo, therefore excellently promoting the survival of dopaminergic neurons, with reduced cellular degeneration, denser Nissl substance and increased tyrosine hydroxylase expression, accompanied by obviously alleviated motor and non-motor symptoms. Pu-Exos-PR were shown as a promising exosome with outstanding biocompatibility, efficient incorporation of bioactive agents, and unique feature in penetration through both nasal tissue and blood brain barrier, inaugurating new avenues to brain-targeting delivery for biomacromolecules for PD therapy. This study also casts new insight on the plant-derived exosomes as next generation of cell homogenous nanoplatforms with high efficiency and biosafety for drug delivery and therapy of brain diseases.

For malignant tumor phototherapy, current biomolecules-based materials face challenges such as limited tissue penetration, insufficient tumor accumulation, and overlook of the unique benefits of chirality, thus hampering their phototherapeutic efficiency. Herein, we introduce a novel near-infrared circularly polarized (NIR-CP) light-responsive hybrid CuInSe₂@ZnS (CISe@ZnS) quantum dots (QDs) hydrogel (QDs@L/D-Gel), which showcases distinctive NIR chiroptical activity, highly enhanced tumor retention, and superior photothermal/photodynamic properties. Particularly, the QDs@L-Gel exhibits a prominently improved photothermal conversion efficiency (PCE) of 43 % and elevated reactive oxygen species (ROS) upon 808-nm CP light irradiation, outperforming those of linearly polarized light directly emitted from a laser device. Moreover, a remarkably enhanced phototherapeutic efficacy (tumor inhibition rate = 83 %) can be achieved for QDs@L-Gel treated mice after 808-nm CP light treatment, without any toxic side effects. Our findings highlight the importance of supramolecular chirality in NIR-CP-mediated phototherapy, thereby paving a new avenue for more advanced and effective tumor treatment in clinical applications.

To date, there has been significant interest in determining the extent to which different anticancer drugs delivered through identical nanodrug delivery systems have different drug permeabilities in tumor microenvironment (TME) and thus variable anticancer effects. In this study, we measured variations in drug permeability and the quantity of anticancer drugs delivered through the same nanodrug delivery system in the TME from intratumoral blood vessels. Measurements were conducted with respect to therapy type, including chemotherapy and photodynamic therapy. The results revealed significant variations in drug permeability depth and anticancer drug amounts depending on the drug target and therapeutic approach. Hypoxic cancer cells are the main targets of anticancer drugs as a cause of cancer recurrence; however, anticancer drugs do not reach these cells because of their limited drug permeability. To the best of our knowledge, this is the first study to present a bioenzyme-conjugated nanodrug delivery system with excellent drug permeability that can effectively kill hypoxic cancer cells in the TME.