Monovalent SARS-COV-2 mRNA vaccine using optimal UTRs and LNPs is highly immunogenic and broadly protective against Omicron variants.

The emergence of highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that are resistant to the current COVID-19 vaccines highlights the need for continued development of broadly protective vaccines for the future. Here, we developed two messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines, TU88mCSA and ALCmCSA, using the ancestral SARS-CoV-2 spike sequence, optimized 5' and 3' untranslated regions (UTRs), and LNP combinations. Our data showed that these nanocomplexes effectively activate CD4+ and CD8+ T cell responses and humoral immune response and provide complete protection against WA1/2020, Omicron BA.1 and BQ.1 infection in hamsters. Critically, in Omicron BQ.1 challenge hamster models, TU88mCSA and ALCmCSA not only induced robust control of virus load in the lungs but also enhanced protective efficacy in the upper respiratory airways. Antigen-specific immune analysis in mice revealed that the observed cross-protection is associated with superior UTRs [Carboxylesterase 1d (Ces1d)/adaptor protein-3ß (AP3B1)] and LNP formulations that elicit robust lung tissue-resident memory T cells. Strong protective effects of TU88mCSA or ALCmCSA against both WA1/2020 and VOCs suggest that this mRNA-LNP combination can be a broadly protective vaccine platform in which mRNA cargo uses the ancestral antigen sequence regardless of the antigenic drift. This approach could be rapidly adapted for clinical use and timely deployment of vaccines against emerging and reemerging VOCs.

Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response.

The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8+ T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen-bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2180-188)-encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti-programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.

Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis.

Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography-mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 (Tsc2) mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.

Synthesis of Partially Hydrogenated Cycloparaphenylenes with Bent and Fused Structures Bearing Armchair Carbon Nanotube-like Connections.

The Diels-Alder reactions between 2 equiv of (E,E)-1,4-bis(4-bromophenyl)-1,3-butadiene and 1,4-benzoquinone led to the formation of a key intermediate with all four 4-bromophenyl substituents cis to one another. The subsequent nickel-mediated homocoupling reactions then produced partially hydrogenated cycloparaphenylenes, including a molecule bearing two units of tetrahydro[6]cycloparaphenylene (4H[6]CPP) fused together through two 1,4-dimethoxybenzene units in an armchair (6,6)carbon nanotube-like connection. Similarly, two 6H[9]CPPs were connected through three 1,4-dimethoxybenzene units in an armchair (9,9)carbon nanotube-like arrangement. A bent 8H[12]CPP and a bent 12H[18]CPP, which were fused intramolecularly with two and three 1,4-dimethoxybenzene units, respectively, to create the bent structures, were likewise synthesized. A molecule containing a bent 8H[12]CPP fused to a 4H[6]CPP was likewise constructed. The structures of these partially hydrogenated CPPs were established by X-ray structure analysis, NMR spectroscopy, and additional independent synthetic pathways.

Synthesis and Characterization of Functionalized [12]Cycloparaphenylenes Containing Four Alternating Biphenyl and Naphthyl Units.

Functionalized [12]cycloparaphenylenes ([12]CPPs) containing four alternating biphenyl and naphthyl units were synthesized. A macrocyclic furan-containing CPP precursor was used for the Diels-Alder reaction with the parent benzyne or 3,6-dimethoxybenzyne to form the corresponding macrocyclic carbon frameworks. The subsequent reductive deoxygenation of the Diels-Alder adducts with Fe2(CO)9 followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone produced the functionalized [12]CPPs. The effect of macrocyclic ring size on the reaction rate of oxidative aromatization was investigated.

Synthesis of Cycloparaphenylenes Bearing Furan-2,5-diyl or 2,2'-Bifuran-5,5'-diyl Units in the Macrocyclic Structures.

Synthetic pathways to furan-containing cycloparaphenylenes (CPPs) as molecular nanohoops bearing 10, 12, and 15 aromatic units including furan-2,5-diyl or 2,2'-bifuran-5,5'-diyl units have been developed. The X-ray structures of a partially hydrogenated bifuran-containing CPP precursor and the corresponding fully aromatized bifuran-containing CPP were obtained to allow the determination of their conformational arrangements in the crystal lattice. The optical and electrochemical properties of the furan-containing CPPs were investigated.

Synthesis of tricyclic quinazolinones via intramolecular cyclization of 3-(2-aminoalkyl)-2-(phenylamino)quinazolin-4(3H)-ones.

Bioactive tricyclic quinazolines class of 3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-ones I and 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones II were synthesized by the formic acid-catalyzed intramolecular cyclization of 3-(2-aminoalkyl)-2-(phenylamino)quinazolin-4(3H)-ones 1 in high yields. A plausible mechanism of the cyclization step is proposed.

Dearomative cyclization of pyridines/isoquinolines with cyclopropenones: access to indolizinones and benzo-fused indolizinones.

Dearomatization reactions provide a rapid approach to construct complicated molecules that are difficult to synthesize by traditional methods from simple aromatic compounds. Herein, we report an efficient dearomative [3+2] cycloaddition reaction of 2-alkynyl pyridines with diarylcyclopropenones, leading to the synthesis of densely functionalized indolizinones in moderate to good yields under metal-free conditions. In addition, this strategy can also be employed in dearomative cyclization of isoquinolines to access a variety of benzo-fused indolizinones. Density functional theory (DFT) calculations revealed that an appropriate substituent at the 2-position of pyridine is crucial to the dearomatization process.

Rhodium-embedded UV photodetectors based on localized surface plasmon resonance on AlN/GaN.

We report a remarkably enhanced responsivity of metal-semiconductor-metal photodetectors embedded with a large-scale periodicity and highly uniform rhodium nanoparticle array based on localized surface plasmon resonance. In this study, we used theoretical simulations of the absorption, scattering, and extinction behaviors, as well as the near electromagnetic field distributions to predict the plasmon resonance wavelength of quasi-triangular-shaped rhodium nanoparticles. More specifically, we successfully implemented a hexagonal close-packed structure with the individual quasi-triangular-shaped rhodium nanoparticle on the AlN/GaN structure by self-assembly nanosphere technology. The characterization results showed that the device embedded with rhodium nanoparticles had a reduced dark current of 7 × 10-14 A, and the maximum responsivity was shifted to a longer wavelength of approximately 310 nm compared to the device without rhodium nanoparticles. Moreover, at a wavelength of 324 nm, the enhancement ratio of the responsivity was as high as 56. Our study makes a significant contribution to the literature with a highly uniform, large-scale distributed rhodium nanoparticle array for enhancing the performance of AlGaN-based photodetectors in the UV region.

In Vitro Engineering Chimeric Antigen Receptor Macrophages and T Cells by Lipid Nanoparticle-Mediated mRNA Delivery.

Chimeric antigen receptor (CAR)-engineered adoptive cell therapy marks a revolution in cancer treatment based on the highly successful responses to CAR T cell therapy in the treatment of blood cancers. Due to the versatile structure of CARs, this technology can be easily adapted to other immune cell types, including macrophages and NKs, and applied in the treatment of many other cancers. However, high costs and fatal adverse effects represent significant concerns for future development. In vitro transcribed (IVT) mRNA therapeutics, which possess a high safety profile and straightforward production methods, could provide a useful alternative for CAR cell construction. However, the low stability and transfection efficiency of IVT-mRNA in immune cells limit further applications. In this work, we successfully engineered CAR macrophages (CAR-Ms) and CAR T cells with CAR mRNA using lipid nanoparticles (LNPs). Both the LNP formulations and mRNA modifications were optimized for in vitro mRNA transfection. More importantly, the CAR macrophages and CAR T cells both demonstrated significant cytotoxic effects on B lymphoma in vitro, underscoring the great potential of mRNA-engineered adoptive cell therapy.

Acute urinary retention secondary to perforated diverticulitis misdiagnosed as acute prostatitis.

Abdominal abscess resulting from a perforated diverticulitis has never been reported as a cause of acute urinary retention. Our patient is the first case to be reported. Because of the atypical presentation, he was initially misdiagnosed and treated as having acute prostatitis. Emergency physicians should have a high index of suspicion. Detailed history, abdominal sonography, and digital examination are helpful in diagnosing this disease.

Syntheses and Structures of Functionalized [9]Cycloparaphenylenes as Carbon Nanohoops Bearing Carbomethoxy and N-Phenylphthalimido Groups.

Functionalized [9]cycloparaphenylenes ([9]CPPs) bearing nine aromatic units in the macrocyclic structures were synthesized. The macrocyclic structures were substituted with carbomethoxy or N-phenylphthalimido groups. The Diels-Alder reaction of (E,E)-1,4-bis(4-bromophenyl)-1,3-butadiene or a related diene with dimethyl acetylenedicarboxylate followed by the nickel-mediated homocoupling reactions and oxidative aromatization produced the functionalized [9]CPPs. Treatment of a resultant [9]CPP with aniline or 1,4-diaminobenzene gave the corresponding N-phenylphthalimides. The X-ray structure of a [9]CPP bearing six carbomethoxy groups was obtained.

Functionalized carbon nanohoops: synthesis and structure of a [9]cycloparaphenylene bearing three 5,8-dimethoxynaphth-1,4-diyl units.

A functionalized [9]cycloparaphenylene ([9]CPP) bearing three evenly spaced 5,8-dimethoxynaphth-1,4-diyl units and two macrocyclic [6]CPP precursors have been synthesized. The Diels-Alder reaction between (E,E)-1,4-bis(4-bromophenyl)-1,3-butadiene and 1,4-benzoquinone followed by methylation produces cis-5,8-bis(4-bromophenyl)-5,8-dihydro-1,4-dimethoxynaphthalene as the key intermediate for the construction of the hooplike structures. The nickel-mediated homocoupling reactions followed by aromatization led to the functionalized [9]CPP.