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Biofilms and intracellular survival tremendously help Helicobacter pylori (H. pylori) escape from antibacterial agents attacking, therefore issuing extreme challenges to clinical therapies. Herein, we constructed fucoidan (FU)-coated nanoparticles (FU/ML-LA/EB NPs) via simple self-assembly of biguanide derivative (metformin-linoleic acid, ML) and linoleic acid (LA), encapsulating urease inhibitor ebselen (EB) instead of antibiotics to take antibacterial effect. Negatively charged FU/ML-LA/EB NPs easily penetrated through the gastric mucus layer to arrive at infection sites, then eradicated extracellular polymeric substances (EPS) to destroy H. pylori biofilms structure. After strengthening bacterial membrane permeability, the nanoparticles could enter H. pylori and kill bacteria by inhibiting the activity of urease. FU/ML-LA/EB NPs also entered H. pylori-infected host cells through receptor-mediated internalization, in which they activated AMPK to recover lysosomal acidification for killing intracellular H. pylori. Additionally, FU/ML-LA/EB NPs alleviated oxidative stress, hence reducing gastric mucosal damage and cutting off the pathways of carcinogenesis. Notably, H. pylori burden after FU/ML-LA/EB NPs treatment was reduced to a great extent in vivo, which was significantly lower than that after treatment with clinical therapy. Antibiotics-free FU/ML-LA/EB NPs improving bacterial eradication and alleviating oxidation stress made it a powerful approach against H. pylori., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mitochondria play a central role in cancer progression and tumor metastasis, and nanomedicines targeting mitochondria have emerged as a promising strategy for tumor therapy. However, mitochondria targeting strategies have not been widely explored in the inhibition of tumor metastasis, and they have disadvantages of complicated preparation, low drug loading, systemic toxicity of the carriers and poor accumulation at tumor sites. Here we firstly developed self-assembled nanodrugs with a high drug loading (∼68%) comprised of a berberine derivative (Ber) and doxorubicin (Dox) by a simple nano-precipitation method, which successfully altered the target location of Dox from the nucleus to mitochondria and therefore inhibited the proliferation, invasion and migration of MDA-MB-231 cells by triggering cell apoptosis. The surface of nanodrugs was modified with DSPE-PEG-folic acid (DSPE-PEG-FA) and hyaluronic acid (HA) for precise tumor recognition and enhanced accumulation (HA-FA-BD NDs). Upon arrival at the tumor site with the help of the enhanced permeability and retention (EPR) effect, the partial degradation of HA by hyaluronidase (HAase) at the tumor site allowed the partial exposure of the positively charged FA-BD NDs to the cells, then nanodrugs would accumulate and enter tumor cells by dual binding to both folic acid (FA) and CD-44 receptors. Once internalized into lysosomes, both the HA outer shell and DSPE-PEG-FA of nanodrugs were degraded or decomposed completely to expose positively charged BD NDs. Driven by delocalized lipophilic cations, nanodrugs could escape from lysosomes and reach mitochondria to induce a cascade reaction and finally cell apoptosis, as well as suppressing matrix metalloprotease (MMP)-2 and -9 activities and finally cell migration and invasion. In a xenograft mice model of MDA-MB-231 breast cancer cells, the nanodrugs repaired the defects in Mfn 1/Drp 1 mitochondrial proteins, suppressed the activity of MMP-2 and -9, and significantly inhibited tumor cell proliferation and pulmonary metastasis. Our study showed a promising strategy for the treatment of metastatic breast cancer by targeting mitochondria followed by enhanced apoptosis.

The resistance of Helicobacter pylori (H. pylori) to conventional antibiotic treatments becomes prevalent recently. The biofilm formation was found to be highly correlated with the antibiotic resistance of H. pylori in the last decades. Moreover, H. pylori colonizes on the digestive tract epithelium located under the mucus layers, which further reduces therapeutic efficacy as mucus layers trap and remove exogenous substances including drugs. Herein, we reported a novel lipid polymer nanoparticles (LPNs) to overcome both biofilm and mucus layers obstruction. LPNs employed chitosan nanoparticle (CS NPs) as the core, mixed lipid layer containing rhamnolipids (RHL) as the shell and the surface of LPNs was further modified with DSPE-PEG2000 to improve hydrophilicity. Clarithromycin (CLR), a first-line drug for H. pylori infection, was encapsulated in LPNs. LPNs, especially the formulation utilizing 100% of RHL as the lipid shell, exhibited excellent eradicating ability to H. pylori biofilm, which was mainly reflected in the significant reduction of biofilm biomass and viability, destruction of biofilm architecture and elimination of extracellular polymeric substances (EPS). The anti-biofilm activities of LPNs are related to: 1) the disrupting effect of RHL on biofilm matrix; 2) antibacterial effects of CLR and CS NPs on biofilm bacteria and 3) inhibitory effects of CS NPs and RHL on bacteria adhesion and biofilm formation. Furthermore, PEGylated LPNs could rapidly penetrate through mucus without interacting with mucins and effectively eradicate H. pylori biofilm under mucus layer. In conclusion, a novel approach of drug-containing LPNs that could penetrate through mucus layers and effectively eradicate H. pylori biofilm provides new ways to treat persistent H. pylori infections., (Copyright © 2019 Elsevier B.V. All rights reserved.)