Immunoregulatory Engineering of Semiconducting Charge-reversal Nanoantioxidant for Ameliorating Cancer Radioimmunotheranostics.

Radiotherapy (RT) is a crucial clinical modality for cancer. However, non-selectivity, toxicity to normal tissues, and radio-resistance severely limit RT applications. In this study, we developed a versatile X-ray theranostic nano-antioxidant (XTN) to prevent normal tissues from oxidative damage and induce systematic and robust anticancer immunity. XTN owns NIR-II photoacoustic imaging properties for precise discrimination of the tumor margin through, thereby improving the accuracy of RT. Additionally, XTN is a nano-antioxidant to enhance the cell viability of normal cells after irradiation. Most importantly, XTN scavenges ROS in the TME to preserve the stimulatory activity of released high mobility group protein B1 to dendritic cells and recover T cells' immune function. Meanwhile, XTN achieves charge-reversal specifically releasing an immunomodulator (demethylcantharidin, DMC) in the acidic TME. Moreover, the specifically released DMC inhibits protein phosphatase-2A activity and reduces regulatory T-cell differentiation. In the bilateral 4T1 tumor model, XTN-mediated radioimmunotherapy remarkably boosts a systemic antitumor immune response and induces durable immunological memory against tumor growth. This article is protected by copyright. All rights reserved.

Toward Type I/II ROS Generation Photoimmunotherapy by Molecular Engineering of Semiconducting Perylene Diimide.

As prospective phototheranostic agents for cancer imaging and therapy, semiconducting organic molecule-based nanomedicines are developed. However, near-infrared (NIR) emission, and tunable type I (O2 • -) and type II (1O2) photoinduced reactive oxygen species (ROS) generation to boost cancer photoimmunotherapy remains a big challenge. Herein, a series of D-π-A structures, NIR absorbing perylene diimides (PDIs) with heavy atom bromide modification at the bay position of PDIs are prepared for investigating the optimal photoinduced type I/II ROS generation. The heavy atom effect has demonstrated a reduction of molecular ∆EST and promotion of the intersystem crossing processes of PDIs, enhancing the photodynamic therapy (PDT) efficacy. The modification of three bromides and one pyrrolidine at the bay position of PDI (TBDT) has demonstrated the best type I/II PDT performance by batch experiments and theoretical calculations. TBDT based nanoplatforms (TBDT NPs) enable type I/II PDT in the hypoxic tumor microenvironment as a strong immunogenic cell death (ICD) inducer. Moreover, TBDT NPs showing NIR emission allow in vivo bioimaging guided phototherapy of tumor. This work uses novel PDIs with adjustable type I/II ROS production to promote antitumor immune response and accomplish effective tumor eradication, consequently offering molecular guidelines for building high-efficiency ICD inducers.

Force spectra of single bacterial amyloid CsgA nanofibers.

CsgA is a major protein subunit of Escherichia coli biofilms and plays key roles in bacterial adhesion and invasion. CsgA proteins can self-assemble into amyloid nanofibers, characterized by their hierarchical structures across multiple length scales, outstanding strength and their structural robustness under harsh environments. Here, magnetic tweezers were used to study the force spectra of CsgA protein at fibril levels. The two ends of a single nanofiber were directly connected between a magnetic bead and a glass slide using a previously reported tag-free method. We showed that a wormlike chain model could be applied to fit the typical force-extension curves of CsgA nanofibers and to estimate accordingly the mechanical properties. The bending stiffness of nanofibers increased with increasing diameters. The changes in extension of single CsgA fibers were found to be up to 17 fold that of the original length, indicating exceptional tensile properties. Our results provide new insights into the tensile properties of bacterial amyloid nanofibers and highlight the ultrahigh structural stability of the Escherichia coli biofilms.