Amphiphilic polymeric nanodrug integrated with superparamagnetic iron oxide nanoparticles for synergistic antibacterial and antitumor therapy of colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies that can be influenced by Fusobacterium nucleatum (Fn), a bacterium that promotes tumor development and chemoresistance, resulting in limited therapeutic efficacy. Traditional antibiotics cannot effectively eliminate Fn at tumor site due to issues like biofilm formation, while chemotherapy alone fails to suppress tumor progression. Therefore, the development of new methods to eliminate Fn and promote antitumor efficacy is of great significance for improving the outcome of CRC treatment. Herein, we developed a nanodrug (OPPL) that integrates oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) and an amphiphilic polymer (PPL) to deliver the platinum prodrug and antimicrobial lauric acid (LA) for enhancing the treatment of CRC. We demonstrated that OPPL can synergistically enhance antibacterial and biofilm disruption activities against Fn along with the antimicrobial LA by producing reactive oxygen species (ROS) through its peroxidase-like activity. Furthermore, the OPPL nanodrug can increase intracellular ROS, promote lipid peroxides and deplete glutathione, leading to ferroptosis. By combining chemotherapy and induced ferroptosis, the OPPL nanodrug exhibited high cytotoxicity against CRC cells. In vivo studies showed that the OPPL nanodrug could enhance tumor accumulation, enable magnetic resonance imaging, suppresse tumor growth, and inhibit growth of intratumor Fn. These results suggest that OPPL is an effective and promising candidate for the treatment of Fn-infected CRC. STATEMENT OF SIGNIFICANCE: The enrichment of Fusobacterium nucleatum (Fn) in colorectal cancer is reported to exacerbate tumor malignancy and is particularly responsible for chemoresistance. To this respect, we strategically elaborated multifaceted therapeutics, namely OPPL nanodrug, combining oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) with a polymer containing a platinum prodrug and antimicrobial lauric acid. The O-SPION components exert distinctive peroxidase-like activity, capable of stimulating Fenton reactions selectively in the tumor microenvironment, consequently accounting for the progressive production of reactive oxygen species. Hence, O-SPIONs have been demonstrated to not only supplement the antimicrobial activities of lauric acid in overcoming Fn-induced chemoresistance but also stimulate potent tumor ferroptosis. Our proposed dual antimicrobial and chemotherapeutic nanodrug provides an appreciable strategy for managing challenging Fn-infected colorectal cancer.

In situ-activated photothermal nanoplatform for on-demand NO gas delivery and enhanced colorectal cancer treatment.

The naturally evolved and intestinal pathogenic Fusobacterium nucleatum (Fn)-induced drug resistance profoundly impaired the efficacy of chemotherapy against colorectal cancer (CRC). Alternative treatment modalities against Fn-associated CRC are desperately needed. Herein, we engineer an in situ-activated anti-tumor and antibacterial nanoplatform (Cu2O/BNN6@MSN-Dex) to allow photoacoustic (PA) imaging-guided photothermal and NO gas combinatorial therapy for enhanced Fn-associated CRC treatment. The nanoplatform is constructed by loading cuprous oxide (Cu2O) and nitric oxide (NO) donor (BNN6) into dextran-decorated mesoporous silica nanoparticles (MSN), which is finally surface-functionalized with dextran via dynamic boronate linkage. Cu2O can be sulfuretted in situ by endogenous hydrogen sulfide overexpressed in CRC to produce copper sulfide with remarkable PA and photothermal properties, enabling the generation of NO from BNN6 under 808 nm laser irradiation, which is eventually triggered to release by multiple biological cues in the tumor microenvironment. Cu2O/BNN6@MSN-Dex exhibits superior biocompatibility, as well as H2S-triggered near-infrared-controlled antibacterial and anti-tumor performance in vitro and in vivo via photothermal and NO gas combination therapy. Furthermore, Cu2O/BNN6@MSN-Dex provokes systemic immune responses, thereby promoting anti-tumor efficacy. This study provides a conbinational strategy to effectively inhibit tumors and intratumor pathogens for enhanced CRC treatment.

In Situ Sprayed Biotherapeutic Gel Containing Stable Microbial Communities for Efficient Anti-Infection Treatment.

Systematic administration of antibiotics to treat infections often leads to the rapid evolution and spread of multidrug-resistant bacteria. Here, an in situ-formed biotherapeutic gel that controls multidrug-resistant bacterial infections and accelerates wound healing is reported. This biotherapeutic gel is constructed by incorporating stable microbial communities (kombucha) capable of producing antimicrobial substances and organic acids into thermosensitive Pluronic F127 (polyethylene-polypropylene glycol) solutions. Furthermore, it is found that the stable microbial communities-based biotherapeutic gel possesses a broad antimicrobial spectrum and strong antibacterial effects in diverse pathogenic bacteria-derived xenograft infection models, as well as in patient-derived multidrug-resistant bacterial xenograft infection models. The biotherapeutic gel system considerably outperforms the commercial broad-spectrum antibacterial gel (0.1% polyaminopropyl biguanide) in pathogen removal and infected wound healing. Collectively, this biotherapeutic strategy of exploiting stable symbiotic consortiums to repel pathogens provides a paradigm for developing efficient antibacterial biomaterials and overcomes the failure of antibiotics to treat multidrug-resistant bacterial infections.

Harnessing in situ glutathione for effective ROS generation and tumor suppression via nanohybrid-mediated catabolism dynamic therapy.

The overexpression of glutathione (GSH) in cancer cells has long been regarded as the primary obstacle for reactive oxygen species (ROS)-involved anti-tumor therapies. To solve this issue, a ferric ion and selenite-codoped calcium phosphate (Fe/Se-CaP) nanohybrid here is fabricated to catabolize endogenous GSH, instead of directly deleting it, to trigger a ROS storm for tumor suppression. The selenite component in Fe/Se-CaP can catabolize GSH to superoxide anion (O2•-) and hydroxyl radicals (•OH) via cascade catalytic reactions, elevating oxidative stress while destroying antioxidant system. The doped Fe can further catalyze the soaring hydrogen peroxide (H2O2) originated from O2•- to •OH via Fenton reactions. Collectively, Fe/Se-CaP mediated self-augmented catabolism dynamic therapy finally induces apoptosis of cancer cells owing to the significant rise of ROS and, combined with CaP adjuvant, evokes adaptive immune responses to suppress tumor progression, providing an innovative train of thought for ROS-involved anti-tumor therapies.

Ag-Conjugated graphene quantum dots with blue light-enhanced singlet oxygen generation for ternary-mode highly-efficient antimicrobial therapy.

The increasing prevalence of antibiotic resistance highlights the need for new antibacterial drugs and, in particular, the development of alternative approaches such as photodynamic therapy (PDT) and photothermal therapy (PTT) to manage this growing issue. In the present study, a broad-spectrum antibacterial system was produced in which Ag nanoparticle-conjugated graphene quantum dots (GQD-AgNP) were utilised as a blue light-enhanced nanotherapeutic for efficient ternary-mode antimicrobial therapy. The successful conjugation of AgNPs onto the surface of GQDs can significantly improve the production of reactive oxygen species in light-activatable GQDs and the transformation of light energy to hyperthermia with high efficiency. There was a remarkable increase in the sample temperature of nearly 40 °C via photoexcitation after only 10 min of 450 nm laser exposure (14.2 mW cm-2). The hybrids exhibited much more efficient bactericidal capability against both Gram-negative and Gram-positive bacteria compared with GQDs alone, using 450 nm light irradiation. This is likely a consequence of their enhanced PDT, concomitant PTT, and the synergistic function of AgNPs. The antibacterial mechanism of the new-style nanocomposites was found to irreversibly destroy the bacterial membrane structure, leading to the leaking out of the cytoplasmic contents and the death of the bacteria. At low doses, the biocompatible GQD-AgNP hybrids promoted healing in bacteria-infected rat wounds, with negligible adverse impact to the normal tissue, indicating a promising future for combined photodynamic and photothermal antibacterial applications in clinical medicine.

A Biomimetic Non-Antibiotic Approach to Eradicate Drug-Resistant Infections.

The chronic infections by pathogenic Pseudomonas aeruginosa (P. aeruginosa) remain to be properly addressed. In particular, for drug-resistant strains, limited medication is available. An in vivo pneumonia model induced by a clinically isolated aminoglycoside resistant strain of P. aeruginosa is developed. Tobramycin clinically treating P. aeruginosa infections is found to be ineffective to inhibit or eliminate this drug-resistant strain. Here, a newly developed non-antibiotics based nanoformulation plus near-infrared (NIR) photothermal treatment shows a remarkable antibacterial efficacy in treating this drug-resistant pneumonia. The novel formulation contains 50-100 nm long nanorods decorated with two types of glycomimetic polymers to specifically block bacterial LecA and LecB lectins, respectively, which are essential for bacterial biofilm development. Such a 3D display of heteromultivalent glycomimetics on a large scale is inspired by the natural strengthening mechanism for the carbohydrate-lectin interaction that occurs when bacteria initially infects the host. This novel formulation shows the most efficient bacteria inhabitation and killing against P. aeruginosa infection, through lectin blocking and the near-infrared-light-induced photothermal effect of gold nanorods, respectively. Collectively, the novel biomimetic design combined with the photothermal killing capability is expected to be an alternative treatment strategy against the ever-threatening drug-resistant infectious diseases when known antibiotics have failed.

Therapeutic nanoplatforms with bacteria-specific activation for directional transport of antibiotics.

An entirely new strategy is explored for directional transport delivery of antibiotics to bacteria utilizing a bacteria-activated nanoplatform. The nanoplatform can effectively prevent the premature leakage of the therapeutic payload, but release was triggered when the nanoplatforms adhere to bacteria, promising potential applications for the delivery of a wide-range of antimicrobials.