Synergistic antibacterial attributes of copper-doped polydopamine nanoparticles: an insight into photothermal enhanced antibacterial efficacy.

Antibiotic-resistant bacteria and associated infectious diseases pose a grave threat to human health. The antibacterial activity of metal nanoparticles has been extensively utilized in several biomedical applications, showing that they can effectively inhibit the growth of various bacteria. In this research, copper-doped polydopamine nanoparticles (Cu@PDA NPs) were synthesized through an economical process employing deionized water and ethanol as a solvent. By harnessing the high photothermal conversion efficiency of polydopamine nanoparticles (PDA NPs) and the inherent antibacterial attributes of copper ions, we engineered nanoparticles with enhanced antibacterial characteristics. Cu@PDA NPs exhibited a rougher surface and a higher zeta potential in comparison to PDA NPs, and both demonstrated remarkable photothermal conversion efficiency. Comprehensive antibacterial evaluations substantiated the superior efficacy of Cu@PDA NPs attributable to their copper content. These readily prepared nano-antibacterial materials exhibit substantial potential in infection prevention and treatment, owing to their synergistic combination of photothermal and spectral antibacterial features.

Peripheral Polyfunctional PD1+ CD8+ T cells demonstrated strong immune protection in non-small cell lung cancer.

Higher frequencies of polyfunctional PD1+ CD8+ T cells exhibited a stronger capacity to kill tumor cells in vitro and in vivo experiments. These results suggested that peripheral polyfunctional PD1+ CD8+ T cells demonstrated strong immune protection. This study also provided a potential combined treatment strategy with anti-PD1 and CAR-T therapy.

circ_0004140 promotes LUAD tumor progression and immune resistance through circ_0004140/miR-1184/CCL22 axis.

Lung adenocarcinoma (LUAD) is a highly prevalent cancer with high mortality. Immune resistance and tumor metastasis are the pivotal factors for the promotion of LUAD. CircRNAs have been revealed a crucial pre-clinical diagnostic and therapeutic potentials in LUAD. Herein, we identify a novel circRNA (circ_0004140), derived from the oncogene YAP1, which is up-regulated in LUAD. The high expression of circ_0004140 is correlated with poor prognosis and CTL cells dysfunction in LUAD patients. Knockdown of circ_0004140 regulated LUAD cells proliferation, migration, and apoptosis. Mechanistically, circ_0004140 served as a sponge of miR-1184 targeting C-C motif chemokine ligand 22(CCL22). Overexpression of CCL22 reversed the inhibitory effect induced by si-circ_0004140 on cells proliferation and migration. Moreover, we also revealed that elevated circ_ooo4140 was related to cytotoxic lymphocyte exhaustion, and a combination therapy of C-021 (CCL22/CCR4 axis inhibitor) and anti-PD-1 attenuated LUAD promotion and immune resistance. In conclusion, circ_0004140 may drive resistance to anti-PD-1 immunotherapy, providing a novel potential therapeutic target for LUAD treatment.

Highly Potent Immunotoxins Targeting the Membrane-distal N-lobe of GPC3 for Immunotherapy of Hepatocellular Carcinoma.

Glypican-3 (GPC3) has become a compelling target for immunotherapy of hepatocellular carcinoma, including antibody-drug conjugate (ADC), and ADC-like immunotoxin. To investigate the impact of epitopes on the potency of ADCs, current study generated a large panel of chicken monoclonal antibodies (mAbs) that targeted 12 different and over-lapping epitopes on GPC3. These mAbs demonstrated a very high affinity with Kd values in the range of 10-9-10-14 M, and the highest affinity (Kd value of 0.0214 pM) was 40-fold higher than the previously generated high-affinity mAb YP7 (Kd value of 0.876 nM). Additionally, these mAbs exhibited excellent thermostability with Tm values in the range of 45-82 °C. As a proof-of-concept study for ADC, we made immunotoxins (scFv fused with PE24, the 24-kDa cytotoxic domain of Pseudomonas exotoxin A) based on these mAbs, and we found that immunotoxins targeting the N-lobe of GPC3 were overall much more potent than those targeting the C-lobe and other locations. One representative N-lobe-targeting immunotoxin J80A-PE24 demonstrated 3 to 13-fold more potency than the hitherto best immunotoxin HN3-PE24 that was previously developed. J80A-PE24 could suppress tumor growth much greater than HN3-PE24 in a xenograft mouse model. Combination of J80A-PE24 with an angiogenesis inhibitor FGF401 showed additive effect, which dramatically shrank tumor growth. Our work demonstrated that, due to high affinity, excellent thermostability and potency, chicken mAbs targeting the N-lobe of GPC3 are appealing candidates to develop potent ADCs for immunotherapy of liver cancer.

Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice.

Hepatocellular carcinoma (HCC) is a world leading cause of cancer-related mortality, and currently no curative treatment for advanced HCC is available. Glypican-3 (GPC3) is an attractive target for HCC immunotherapy. This study explored the efficacy of six GPC3-targeted bispecific antibodies, alone or in combination with chemotherapeutic drug Irinotecan, for the treatment of HCC. The bispecific antibodies were constructed using three different structures, knob-into-hole (KH), scFv-scFv-hFc, and scFv-hFc-scFv, where CD3-targeting mAb OKT3 (scFv) was paired with two representative GPC3 mAbs hYP7 (scFv) and HN3 (VH only) that target different epitopes. The In vitro cell killing assay revealed that all bispecific antibodies efficiently killed GPC3 positive cancer cells, with hYP7-KH, hYP7-OKT3-hFc, and HN3-KH being most potent. In vivo xenograft mouse studies demonstrated that all bispecific antibodies suppressed tumor growth similarly, with hYP7-OKT3-hFc performing slightly better. Combination of hYP7-OKT3-hFc with Irinotecan dramatically improved the efficacy and arrested tumor growth of HepG2, Hep3B, and G1 in xenograft mice. Our results demonstrated that the cell surface proximal bispecific antibody hYP7-OKT3-hFc was superior in terms of potency and the GPC3-targeted bispecific antibody combined with Irinotecan was much potent to control HCC growth.

Lung Carcinoma Cells Secrete Exosomal MALAT1 to Inhibit Dendritic Cell Phagocytosis, Inflammatory Response, Costimulatory Molecule Expression and Promote Dendritic Cell Autophagy via AKT/mTOR Pathway.

OBJECTIVE: To investigate the potential mechanism underlying the effect of lung carcinoma cell-derived exosomes on dendritic cell function. MATERIALS AND METHODS: C57BL/6 (B6) mice were randomly divided into five groups: control, dendritic cell (DC), DC-NC, DC-siMALAT1, and siMALAT1. Tumor cell proliferation was measured by Ki-67 staining. LLC cells were divided into control, NC, and si-MALAT1 groups, and exosomes secreted by each group were labeled as PEX, PEXN, and PEX-si, respectively. Exosomes and autophagic vacuoles were observed by transmission electron microscopy. MALAT1 expression in LLC, A549, and Beas-2b cells was examined by RT-PCR. The expression of IFN-γ, IL-12, IL-10, and TGF-ß was observed by Elisa assay. Flow cytometry was used to observe the phagocytic function of DCs, costimulatory molecule expression, and T cell proliferation and differentiation. The protein expression of p-AKT, AKT, p-mTOR, mTOR, ALIX, TSG101, and CD63 was detected by Western blot. RESULTS: Compared with Beas-2b cells, MALAT1 expression was significantly increased in both LLC and A549 cells and in their secreted exosomes, and LLC cells showed the highest expression of MALAT1 (P < 0.05). Tumor cell proliferation and tumor volume were significantly decreased in the siMALAT1 and DC-siMALAT1 groups compared to those in the control group. DC phagocytosis, inflammatory response, costimulatory molecule expression, and T cell proliferation in the siMALAT1 and PEX-si groups were significantly enhanced (P < 0.05), while DC autophagy and T cell differentiation were reduced (P < 0.05). The levels of p-AKT, AKT, p-mTOR, and mTOR in the PEX and PEXN groups were increased compared with those in the control group, while those in the siMALAT1 and PEX-si groups were significantly decreased (P < 0.05). CONCLUSION: Inhibition of MALAT1 expression in LLC-derived exosomes promoted DC function and T cell proliferation and suppressed DC autophagy and T cell differentiation, suggesting that MALAT1 inhibition may be a potential strategy for the clinical treatment of lung cancer.