Nanoscale objects are typically internalized by cells into membrane-bounded endosomes and fail to access the cytosolic cell machinery. Whereas some biomacromolecules may penetrate or fuse with cell membranes without overt membrane disruption, no synthetic material of comparable size has shown this property yet. Cationic nano-objects pass through cell membranes by generating transient holes, a process associated with cytotoxicity. Studies aimed at generating cell-penetrating nanomaterials have focused on the effect of size, shape and composition. Here, we compare membrane penetration by two nanoparticle 'isomers' with similar composition (same hydrophobic content), one coated with subnanometre striations of alternating anionic and hydrophobic groups, and the other coated with the same moieties but in a random distribution. We show that the former particles penetrate the plasma membrane without bilayer disruption, whereas the latter are mostly trapped in endosomes. Our results offer a paradigm for analysing the fundamental problem of cell-membrane-penetrating bio-and macro-molecules. Nanomaterials are of great interest for use in biomedicine as imaging tools 1-3 , phototherapy agents 4,5 and gene delivery carriers 6,7 . Their interactions with cell membranes are of central importance for all such applications. For example, many drugdelivery systems are based on the transport of therapeutic agents to the cytosol or nucleus of cells by nanoparticles; efficient delivery must be achieved while avoiding cytotoxicity during passage through cell membranes to reach intracellular target compartments 8,9 . Indeed, membrane penetration by synthetic 10 as well as by biologically derived 11 molecules/particles is currently under intense investigation. Some biomacromolecules, such as cell-penetrating peptides (CPPs), may be capable of penetrating membranes without overt lipid bilayer disruption/poration 12-15 . Likewise, synthetic nanomaterials with very small dimensions (molecules, metal nanoclusters 16 , small dendrimers 10 and carbon nanotubes 17 ) can also pass through cell membranes. However, to the best of our knowledge, no synthetic material larger than a few nanometres in size can pass through membranes without disrupting the integrity of these biological barriers. For example, charged particles (such as cationic quantum dots or dendrimers, mostly assisted by some degree of hydrophobicity) induce transient poration of cell membranes to enter cells, a process associated with cytotoxicity 18 . Alternatively, nanoparticles have been designed to explicitly disrupt endolysosomal membranes to enter the cell by force 19 or enter the cell aided by exogenous agents such as CPP chaperones 20 . In contrast, most nanoparticles are trapped in endosomes 21 and hence do not reach the cytosol.The surface properties of nanomaterials play a critical role in determining the outcome of their interactions with cells 22 . Recently, we found that when gold nanoparticles are coated with binary mixtures of hydrophobic and hydrophilic organic mo...

Polycations that absorb protons in response to the acidification of endosomes can theoretically disrupt these vesicles via the "proton sponge" effect. To exploit this mechanism, we created nanoparticles with a segregated core-shell structure for efficient, noncytotoxic intracellular drug delivery. Cross-linked polymer nanoparticles were synthesized with a pH-responsive core and hydrophilic charged shell designed to disrupt endosomes and mediate drug/cell binding, respectively. By sequestering the relatively hydrophobic pH-responsive core component within a more hydrophilic pH-insensitive shell, nontoxic delivery of small molecules and proteins to the cytosol was achieved in dendritic cells, a key cell type of interest in the context of vaccines and immunotherapy.

One thousand three hundred seventy-nine nasopharyngeal carcinoma (NPC) patients were treated from March 1958 to December 1978. Twenty-two percent had stage I or II and 78% Stage III or IV had lesions. Two hundred twenty-Kv radiographs were used before 1960; and telecobalt was used from 1961 to 1978. Factors influencing the 5-year survival rate favorably are youth of patient, being female, pathologic condition (poorly differentiated carcinoma, 45.1% versus adenocarcinoma, 13%), stage (Stage I, 86%, Stage II, 59.5%; Stage III, 45.8%; Stage IV, 29.2%), decade admitted for treatment in the past (31% in the 1950s, 48.6% in the 1970s), total dose delivered to the nasopharynx (40 to 49 Gy, 46%; 70 to 79 Gy, 54.1%; 90 Gy or more, 64%) and prophylactic radiation to the neck regions (with prophylactic irradiation, 53.8%, without prophylactic irradiation, 23%). This implies that prophylactic radiation of the neck is crucial even without positive clinical metastasis. For those who have a residual tumor in the primary site when 70 Gy has been delivered, the total dose may be boosted to more than 90 Gy with the cone-down technique or on basis of adding 20 Gy to the dose at which the primary lesion disappeared grossly. The common postirradiation complications are: radiation myelitis, trismus, and otitis media. Because disease recurred in some patients after the fifth year, NPC patients should be followed for at least 10 years.

Weaning stress in piglets can lead to poor health outcomes and reduced production.

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We recently described a strategy for intracellular delivery of macromolecules, utilizing pHresponsive 'core-shell' structured gel particles. These crosslinked hydrogel particles disrupt endosomes with low toxicity by virtue of physical sequestration of an endosome-disrupting 'proton sponge' core inside a nontoxic hydrophilic shell. Here we tested the efficacy of this system for cytosolic delivery of a broad range of macromolecular cargos, and demonstrate the delivery of proteins, whole viral particles, or siRNA oligonucleotides into the cytosol of dendritic cells and epithelial cells via core-shell particles. We assessed the functional impact of particle delivery for vaccine applications, and found that cytosolic delivery of protein antigens in dendritic cells via the core-shell particles promotes priming of CD8 + T-cells at 100-fold lower doses than soluble protein.Functional gene knockdown following delivery of siRNA using the particles was demonstrated in epithelial cells. Based on these findings, these materials may be of interest for a broad range of biomedical applications.

The development of simple, rapid-response sensors for water detection in organic solvents is highly desirable in the chemical industry. Here we demonstrate a unique luminescence water sensor based on a dual-emitting europium-organic framework (Eu-MOF), which is assembled from a purposely selected 2-aminoterephthalic acid ligand with responsive fluorescence inherent in its intramolecular charge transfer (ICT) process. This ICT process can be rapidly switched-on in the presence of water owing to its ability to boost and stabilize the ICT state. In contrast, the Eu3+ emission within the framework is insensitive to water and can serve as a reference, thus enabling highly sensitive water detection in a turn-on and ratiometric way. In addition, the significant ratiometric luminescence response induced by water makes Eu-MOF undergo a distinct change of emitting color from red to blue, which is favorable for visual analysis with the naked eye. Sensitive determination of water content (0.05–10% v/v) in various organic solvents is achieved in multiple readouts including ratiometric emission intensity, emission color, or the Commission Internationale de l’Eclairage (CIE) chromaticity coordinate. The present Eu-MOF sensor featuring high sensitivity and reusability, self-calibration, simple fabrication and operation, and capability for real-time and in situ detection is expected to have practical applications in water analysis for industrial processes.

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