Abstract CRISPR/Cas is a revolutionary gene editing technology with wide‐ranging utility. The safe, non‐viral delivery of components would greatly improve future therapeutic We report the synthesis and development zwitterionic amino lipids (ZALs) that are uniquely able to (co)deliver long RNAs including Cas9 mRNA sgRNAs. ZAL nanoparticle (ZNP) low sgRNA doses (15 n m ) reduces protein expression by >90 % in cells. In contrast transient therapies (such as RNAi), we show ZNP enables...

Rheumatoid arthritis (RA) is a common chronic autoimmune inflammatory disease, and its etiology closely related to the overproduction of hypochlorous acid (HClO). However, early detection RA using an activatable near-infrared-II (NIR-II, 1000-1700 nm) fluorescent probe remains challenging. Herein, we first report "OFF-ON" NIR-II named PTA (phenothiazine triphenylamine) for imaging HClO in deep-seated RA. Electron-rich phenothiazine core was utilized as both HClO-recognition moiety precursor...

Significance Liver cancer is a leading cause of death and global health problem. Unfortunately, five small-molecule drugs for hepatocellular carcinoma (HCC) recently failed phase III clinical trials partly because late-stage liver dysfunction amplifies drug toxicity. MicroRNAs (miRNAs) present promising alternative treatment strategy but require development delivery vehicles that can avoid this cancer-induced dysfunction, which exacerbates We overcame challenge by developing dendrimer...

Current photosensitizers (PSs) for photodynamic therapy (PDT) are limited by their low water solubility and tendency to aggregate, near-infrared (NIR) absorption, cancer selectivity. Here, we designed iodinated, water-soluble NIR boron dipyrromethene-based PSs achieve image-guided efficient PDT against in vivo that is enhanced leveraging tumor-specific pH-responsive activation. PEG2k5c-I PEG2k5c-OMe-I localized tumors were activated acidic pH the tumor microenvironment produce 1O2...

The ability to control chemical functionality is an exciting feature of modern polymer science that enables precise design drug delivery systems. Ring-opening polymerization functional monomers has emerged as a versatile method prepare clinically translatable degradable polyesters.1 A variety groups have been introduced into lactones; however, the direct tertiary amine functionalized cyclic esters remained elusive. We report strategy enabled rapid synthesis >130 lipocationic polyesters...

Messenger RNA (mRNA) has recently come into focus as an emerging therapeutic class with great potential for protein replacement therapy, cancer immunotherapy, regenerative medicine, vaccines, and gene editing. However, the lack of effective safe delivery methods impedes broad application mRNA-based therapeutics. We report a robust approach to develop efficient polymeric carriers mRNA. Lead polyesters were identified by in vitro screening 480-member combinatorially modified...

Inflammatory bowel disease (IBD) is a common gastrointestinal inflammatory disease, affecting huge number of people worldwide with increasing morbidity each year. Although the etiology IBD has not been fully elucidated, it understood to be closely related upregulation production NO. Herein, we first report donor–acceptor–donor (D–A–D)-type near-infrared (NIR) fluorescent probe LS-NO for real-time detection NO in by harnessing enhanced intramolecular charge transfer mechanism. exhibited good...

Drug-induced liver injury (DILI) is the most common clinical adverse drug reaction, which closely associated with oxidative stress caused by overproduced reactive oxygen species. Hepatic H2O2, as an important biomarker of DILI, plays a crucial role in progression DILI. However, there remains challenge to develop H2O2-activatable second near-infrared (NIR-II, 1000–1700 nm) small molecular probes both large Stokes shift and long emission wavelength beyond 950 nm. Herein, we developed...

Lipid nanoparticles (LNPs) represent the most clinically advanced nonviral mRNA delivery vehicles; however, full potential of LNP platform is greatly hampered by inadequate endosomal escape capability. Herein, we rationally introduce a disulfide bond-bridged ester linker to modularly synthesize library 96 linker-degradable ionizable lipids (LDILs) for improved in vivo. The top-performing LDILs are composed one 4A3 amino headgroup, four linkers, and 10-carbon tail chains, whose unique...

Abstract It is challenging to develop a near‐infrared (NIR) small molecular photosensitizer for synergistic phototherapy in deep tissues. Herein, first, heavy‐atom‐free NIR hemicyanine (BHcy) 808 nm light‐mediated photodynamic therapy/photothermal therapy (PDT/PTT) anticancer by leveraging the acceptor engineering strategy reported. This endows BHcy with more planar and larger π‐conjugated structure, resulting long absorption/emission at 770/915–1200 as well enhanced singlet oxygen ( 1 O 2 )...

Developing molecular fluorophores with enhanced fluorescence in aggregate state for the second near-infrared (NIR-II) imaging is highly desirable but remains a tremendous challenge due to lack of reliable design guidelines. Herein, we report an aromatic substituent strategy construct bright NIR-II J-aggregates. Introduction electron-withdrawing substituents at 3,5-aryl and meso positions classic boron dipyrromethene (BODIPY) skeleton can promote slip-stacked J-type arrangement further boost...

Conventional cyanine dyes with a symmetric structure are "always-on", which can easily accumulate in the liver and display high background fluorescence, inevitably interfering accurate diagnosis therapy extrahepatic diseases. We herein report platform of NIR-II non-symmetric (NSCyanine) by harnessing strategy, extremely sensitive to pH/viscosity be activated via "dual-key-and-lock" strategy. These NSCyanine low pKa (<4.0) only show weak fluorescence at lysosome pH (key1), however, completely...

Organic dyes with simultaneously boosted near-infrared-II (NIR-II) fluorescence, type I photodynamic therapy (PDT), and photothermal (PTT) in the aggregate state are still elusive due to unclear structure-function relationship. Herein, electron-withdrawing substituents introduced at 5-indolyl positions of BODIPY form tight J-aggregates for enhanced NIR-II fluorescence PDT/PTT. The introduction an electron-rich julolidine group

Significance Ideal cancer therapeutics accurately hit tumors and avoid side effects on healthy cells. We used a patient-derived pair of matched cancer/normal cell lines to discover selective nanoparticles that could deliver cytotoxic siRNA kill cells not normal The finding respond differently the same nanoparticle has profound implications for gene therapy because cell-type specificity drug carriers in vivo alter clinical patient outcomes. Our data suggest selectivity is an underappreciated...

Breast cancer metastasis is the major cause of death in women worldwide. Early detection would save many lives, but current fluorescence imaging probes are limited their ability, particularly bone and liver micrometastases. Herein, that capable tiny (&lt;1 mm) micrometastases liver, lung, pancreas, kidneys, bone, have disseminated from primary site, reported. The influence poly(ethylene glycol) (PEG) chain length on performance water‐soluble, pH‐responsive, near‐infrared...

Abstract CRISPR/Cas is a revolutionary gene editing technology with wide‐ranging utility. The safe, non‐viral delivery of components would greatly improve future therapeutic We report the synthesis and development zwitterionic amino lipids (ZALs) that are uniquely able to (co)deliver long RNAs including Cas9 mRNA sgRNAs. ZAL nanoparticle (ZNP) low sgRNA doses (15 n m ) reduces protein expression by &gt;90 % in cells. In contrast transient therapies (such as RNAi), we show ZNP enables...

We herein report a series of high-brightness pH-activatable near-infrared (NIR) BODIPY probes for high-contrast intravital imaging deep-seated early breast cancer bone metastasis by harnessing the axial substituent effect. These exhibit tunable pKa, higher brightness, and antiquenching capabilities in aqueous solution, which can be simultaneously adjusted steric substituents. The optimized probe BODO-3 bearing dimethyl substituents exhibited pKa value 5.6 brighter NIR fluorescence under...

Fluorescence imaging in the second near-infrared (NIR-II, 1000–1700 nm) region holds great promise for vivo bioimaging. However, it is challenging to develop a brilliant donor–acceptor–donor (D–A–D) type NIR-II fluorophore with maximal absorption beyond 1000 nm aqueous solution. Herein, we report bright D–A–D BOIMPY-based dye (NK1143) peak absorption/emission at 1005/1143 Co-assembly of NK1143, SC12 (intermolecular steric hindrance modulator), and DSPE-PEG2000 effectively inhibits...

Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease, whose etiology intimately related to the overproduction of hypochlorous acid (HClO). Optical monitoring HClO in living body favors real-time diagnosis diseases. However, HClO-activated near-infrared (NIR) fluorescent probes with rapid response and high cell uptake are still lacking. Herein, we report activatable acceptor-π-acceptor (A-π-A)-type NIR probe (

Dysregulated pH has been recognized as a universal tumor microenvironment signature that can delineate tumors from normal tissues. Existing fluorescent probes activate in response to are hindered by either fast clearance (in the case of small molecules) or high liver background emission large particles). There remains need design water-soluble, long circulating, pH-responsive nanoprobes with tumor-to-liver contrast. Herein, we report modular chemical strategy create acidic pH-sensitive and...