Supercharged precision killers: Genetically engineered biomimetic drugs of screened metalloantibiotics against Acinetobacter baumanni.

To eliminate multidrug-resistant bacteria of Acinetobacter baumannii, we screened 1100 Food and Drug Administration-approved small molecule drugs and accessed the broxyquinoline (Bq) efficacy in combination with various metal ions. Antibacterial tests demonstrated that the prepared Zn(Bq)2 complex showed ultralow minimum inhibitory concentration of ~0.21 micrograms per milliliter with no resistance after 30 passages. We then constructed the nano zeolitic imidazolate framework-8 (ZIF-8) as a drug carrier of Zn(Bq)2 and also incorporated the photosensitizer chlorin e6 (Ce6) to trace and boost the antibacterial effect. To further ensure the stable and targeted delivery, we genetically engineered outer membrane vesicles (OMVs) with the ability to selectively target A. baumannii. By coating the ZnBq/Ce6@ZIF-8 core with these OMV, the resulted drug (ZnBq/Ce6@ZIF-8@OMV) exhibited exceptional killing efficacy (>99.9999999%) of A. baumannii. In addition, in vitro and in vivo tests were also respectively carried out to inspect the remarkable efficacy of this previously unknown nanodrug in eradicating A. baumannii infections, including biofilms and meningitis.

The Combination of Membrane Disruption and FtsZ Targeting by a Chemotherapeutic Hydrogel Synergistically Combats Pathogens Infections.

The emergence of multidrug-resistant (MDR) bacteria poses a significant challenge to global health. Due to a shortage of antibiotics, alternative therapeutic strategies are urgently needed. Unfortunately, colistin, the last-resort antibiotic, has unavoidable nephrotoxicity and hepatotoxicity, and its single killing mechanism is prone to drug resistance. To address this challenge, a promising combinatorial approach that includes colistin, a membrane-disrupting antimicrobial agent, and chelerythrine (CHE), a FtsZ protein inhibitor is proposed. This approach significantly reduces antibiotic dose and development of resistance, leading to almost complete inactivation of MDR pathogens in vitro. To address solubility issues and ensure transport, the antimicrobial hydrogel system LNP-CHE-CST@hydrogel, which induced reactive oxygen species (ROS) and apoptosis-like cell death by targeting the FtsZ protein, is used. In an in vivo mouse skin infection model, the combination therapy effectively eliminated MDR bacteria within 24 h, as monitored by fluorescence tracking. The findings demonstrate a promising approach for developing multifunctional hydrogels to combat MDR bacterial infections.

Metallopolymer strategy to explore hypoxic active narrow-bandgap photosensitizers for effective cancer photodynamic therapy.

Practical photodynamic therapy calls for high-performance, less O2-dependent, long-wavelength-light-activated photosensitizers to suit the hypoxic tumor microenvironment. Iridium-based photosensitizers exhibit excellent photocatalytic performance, but the in vivo applications are hindered by conventional O2-dependent Type-II photochemistry and poor absorption. Here we show a general metallopolymerization strategy for engineering iridium complexes exhibiting Type-I photochemistry and enhancing absorption intensity in the blue to near-infrared region. Reactive oxygen species generation of metallopolymer Ir-P1, where the iridium atom is covalently coupled to the polymer backbone, is over 80 times higher than that of its mother polymer without iridium under 680 nm irradiation. This strategy also works effectively when the iridium atom is directly included (Ir-P2) in the polymer backbones, exhibiting wide generality. The metallopolymer nanoparticles exhibiting efficient O2•- generation are conjugated with integrin αvß3 binding cRGD to achieve targeted photodynamic therapy.

Narrow-band polymer dots with pronounced fluorescence fluctuations for dual-color super-resolution imaging.

Super-resolution optical fluctuation imaging (SOFI) produces fast, background-free, super-resolved images by analyzing the temporal fluorescence fluctuations of independent emitters. With sufficient brightness and fluctuations, a higher order of image processing affords a higher resolution and in principle the resolution enhancement is unbounded. However, it is practically challenging to find suitable probes for high-order SOFI. Herein, we report two types of BODIPY-based polymer dots (Pdots) with narrow-band emissions, pronounced fluctuations, and prominent photostability, thus enabling high-order, dual-color SOFI nanoscopy. Single-particle and subcellular SOFI analysis reveals the superior performance of the BODIPY Pdots as compared to conventional streptavidin-conjugated Alexa dyes. In contrast with wide-field images, the spatial resolution (∼57 nm) was enhanced by ∼6.0-fold in 8th-order single-particle SOFI nanoscopy. A spatial resolution (61 nm) was obtained for single microtubules labeled by the BODIPY Pdots, while the majority of the subcellular structures were lost for those labeled by streptavidin-Alexa dyes in 8th-order SOFI. This work indicates the unprecedented performance of Pdot probes for multi-color subcellular SOFI applications.