Search

The combination of ionizable lipids bearing alkyl chains and fluorinated alkyl chains improves the cellular uptake and mRNA expression of lipid nanoparticles.

The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRAS MUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)–conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA–protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non–small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush–ASO conjugate is a promising therapeutic platform for the treatment of KRAS -driven human cancers and warrant further preclinical and clinical development.

The combination of metasurface and holographic technology is the most cutting-edge development, but most of the proposed designs are static and do not allow active changes through external stimulation after fabrication, which takes only a limited part of the advantage provided by metasurface. Here, we propose and demonstrate a switchable hybrid active metasurface hologram in the terahertz (THz) regime composed of dynamic pixels (VO

Interstitial fluid (ISF) provides important information of clinical value and physiological significance beyond blood tests for obtaining more precise health information and disease theranostics. Generally, current strategies are limited to simple extraction with time-consuming follow-up procedures. Facing challenges in efficient and real-time monitoring of target analytes in transdermal ISF, we develop metal-organic framework (MOF)-functionalized microneedle (MN) patches to achieve efficient antibiotics sampling, coupling direct analysis in real time mass spectrometry (DART-MS). The MOF MN microtrapper is constructed in a double-layered structure with a hard core and a better tissue penetration was accomplished. The MOF-based microtrapper manifests good in-vitro and in-vivo antibiotics tracking capability with a semi-quantitative method established. Moreover, the hydrogen-bond driven interaction is clarified by using molecular dynamics simulations (MDS) and related computational analysis. Good penetration safety is confirmed by histological analysis with promising clinical transnationality. We anticipate MOF MN-based microdevices provide a versatile minimally invasive strategy for transdermal ISF extraction and an extendable platform for a range of target molecules monitoring, including drugs, metabolites, biomarkers, et c, with promising clinical transnationality.

Soft lithography provides a convenient and effective method for the fabrication of microdevices with uniform size and shape. However, formation of an embossed, connective film as opposed to discrete features has been an enduring shortcoming associated with soft lithography. Removing this residual layer requires additional postprocessing steps that are often incompatible with organic materials. This limits adaptation and widespread realization of soft lithography for broader applications particularly in drug discovery and drug delivery fields. A novel and versatile approach is demonstrated that enables fabrication of discrete, multilayered, fillable, and harvestable microparticles directly from any thermoplastic polymer, even at very high molecular weights. The approach, isolated microparticle replication via surface-segregating polymer blend mold, utilizes a random copolymer additive, designed with a highly fluorinated segment that, when blended with the mold's matrix, spontaneously orients to the surface conferring an extremely low surface energy and nonwetting properties to the template. The extremely nonwetting properties of the mold are further utilized to load soluble biologics directly into the built-in microwells in a rapid and efficient manner using an innovative screen-printing approach. It is believed that this approach holds promise for fabrication of large-array, 3D, complex microstructures, and is a significant step toward clinical translation of microfabrication technologies.

DNA biotechnology offers intriguing opportunities for amplification-based sensitive detection. However, spatiotemporally-controlled manipulation of signal amplification for in situ imaging of the tumor microenvironment remains an outstanding challenge. Here, we demonstrate a DNA-based strategy that can spatial-selectively amplify the acidic signal in the extracellular milieu of the tumor to achieve specific imaging with improved sensitivity. The strategy, termed mild acidosis-targeted amplification (MAT-amp), leverages the specific acidic microenvironment to engineer tumor cells with artificial DNA receptors through a pH (low) insertion peptide, which permits controlled recruitment of fluorescent amplifiers via a hybridization chain reaction. The acidosis-responsive amplification cascade enables significant fluorescence enhancement in tumors with a reduced background signal in normal tissues, leading to improved signal-to-background ratio. These results highlight the utility of MAT-amp for in situ imaging of the microenvironment characterized by pH disequilibrium.

The implementation of Terahertz (THz) modulation is critical for applications in high-speed wireless communications, security screening and so on. Therefore, it is particularly significant to obtain THz wave modulation devices with stable and flexible performance, easy manipulation of the modulation method, and multi-functionality. Here, we propose a flexible all-dielectric metamaterial by embedding zirconia (ZrO2) microspheres into a vanadium dioxide/polydimethylsiloxane (VO2/PDMS) composite, which can achieve thermal and mechanical tuning of THz wave transmission. When the temperature of the ZrO2/VO2/PDMS metamaterial increases, VO2 changes from the insulating phase to the metallic phase, and the 1st (at 0.304 THz) and 2nd (at 0.414 THz) order magnetic resonances exhibit the tunability of 20 GHz and 15 GHz, respectively. When stretched, the 1st and 2nd order magnetic resonances show the tunability of 12 GHz and 10 GHz, respectively. In the meantime, there are accompanying changes in transmittance at the resonances. The ZrO2/VO2/PDMS all-dielectric metamaterial presented in this work provides an alternative strategy for developing actively tunable, flexible, and versatile THz devices. In addition, it has the merits of simple preparation and low cost, promising large-area and rapid preparation of meta-arrays.

Background: Cancer nanovaccine has become a promising approach for cancer immunotherapy. The major challenge of cancer vaccines is limited efficacy caused by lack of desirable tumor specific antigens (TSA). Chemotherapeutics can trigger immunogenic cell death (ICD) and release TSAs, which initiate tumor-specific immune responses. However, ICD-triggered immune responses are usually not potent enough to eliminate the tumor cells. Herein, we developed liposomal spherical nucleic acids (SNA) that can simultaneously deliver and release doxorubicin (DOX) and CpG oligonucleotides upon biological stimuli in tumors to augment antitumor immune responses. Results: SNA nanoparticle increased DOX accumulation at the tumor tissue to induce tumor cells apoptosis and autophagy to activate both ICD-triggered and autophagy-mediated Th1-type immune responses. Meanwhile, CpG, which was co-delivered with DOX, functioned synergistically to potentiate the antitumor immune responses. These nanoparticles effectively inhibited tumor growth and extended animal survival of a mouse lymphoma model. Conclusions: This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors to improve immunotherapeutic efficacy of nanovaccines.

Chemotherapeutics that can trigger immunogenic cell death (ICD) and release tumor-specific antigens are effective on treating a variety of cancers. The codelivery of chemotherapeutics with adjuvants is a promising strategy to achieve synergistic therapeutic effect. However, low drug loading and complicated preparation of current delivery systems lead to carrier-associated toxicity and immunogenicity. Herein, we developed a facile approach to construct liposomal spherical nucleic acids (SNA) by the self-assembly of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-doxorubicin conjugate and DOPE-matrix metalloproteinases-9 (MMP-9) responsive peptide-CpG conjugate (DOPE-MMP-CpG). Liposomal SNAs efficiently co-delivered DOX and CpG into tumors and released the two drugs upon biological stimuli of MMP-9 enzyme in tumor microenvironment (TME) and high concentration of endogenous glutathione in tumor cells. We demonstrated that liposomal SNA enhanced activation of dendritic cells (DCs), promoted expansion of CD8+ and CD4+ T cells in both tumors and spleen, inhibited tumor growth, and extended animal survival. This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors with synergistic therapeutic effect and reduced side effect. Graphical Abstract

The combination of metasurface and holographic technology is the most cutting-edge development, but most of the proposed designs are static and do not allow active changes through external stimulation after fabrication, which takes only a limited part of the advantage provided by metasurface. Here, we propose and demonstrate a switchable hybrid active metasurface hologram in the terahertz (THz) regime composed of dynamic pixels (VO2-CSRR) and static pixels (Au-CSRR) based on an intelligent algorithm, which can display some/all information in different temperature ranges. In particular, such performance shows excellent potential in the field of optical communication security, making it a promising candidate. To prove this possibility, we propose a scheme for optical information encryption/decryption and transmission, which takes metasurfaces as carriers of encrypted information and state/polarization/positions as the secret key components. Only when the two matches correctly can we get the hidden real information. The security of our proposed scheme has reached an unprecedented level, providing a new road for communication security.

Nanovaccines have emerged as promising alternatives or complements to conventional cancer treatments. Despite the progresses, specific co-delivery of antigen and adjuvant to their corresponding intracellular destinations for maximizing the activation of antitumor immune responses remains a challenge. Herein, a lipid-coated iron oxide nanoparticle is delivered as nanovaccine (IONP-C/O@LP) that can co-deliver peptide antigen and adjuvant (CpG DNA) into cytosol and lysosomes of dendritic cells (DCs) through both membrane fusion and endosome-mediated endocytosis. Such two-pronged cellular uptake pattern enables IONP-C/O@LP to synergistically activate immature DCs. Iron oxide nanoparticle also exhibits adjuvant effects by generating intracellular reactive oxygen species, which further promotes DC maturation. IONP-C/O@LP accumulated in the DCs of draining lymph nodes effectively increases the antigen-specific T cells in both tumor and spleen, inhibits tumor growth, and improves animal survival. Moreover, it is demonstrated that this nanovaccine is a general platform of delivering clinically relevant peptide antigens derived from human papilloma virus 16 to trigger antigen-specific immune responses in vivo.