Personalized Nanovaccines Enhance Lymph Node Accumulation and Reprogram the Tumor Microenvironment for Improved Photodynamic Immunotherapy.

Tumor immunotherapy has emerged as an efficacious therapeutic approach that mobilizes the patient's immune system to achieve durable tumor suppression. Here, we design a photodynamic therapy-motivated nanovaccine (Dex-HDL/ALA-Fe3O4) co-delivering 5-aminolevulinic acid and Fe3O4 nanozyme that demonstrate a long-term durable immunotherapy strategy. After vaccination, the nanovaccine exhibits obvious tumor site accumulation, lymph node homing, and specific and memory antitumor immunity evocation. Upon laser irradiation, Dex-HDL/ALA-Fe3O4 effectively generates reactive oxygen species at the tumor site not only to induce the immunogenic cell death-cascade but also to trigger the on-demand release of full types of tumor antigens. Intriguingly, Fe3O4 nanozyme-catalyzed hydrogen peroxide generated oxygen for alleviating tumor hypoxia and modifying the inhibitory tumor microenvironment, thereby exhibiting remarkable potential as a sensitizer. The intravenous administration of nanovaccines in diverse preclinical cancer models has demonstrated remarkable tumor regression and inhibition of postoperative tumor recurrence and metastasis, thereby enabling personalized treatment strategies against highly heterogeneous tumors.

Effects of extracted oil of fermented Tartary buckwheat on lipid-lowering, inflammation modulation, and gut microbial regulation in mice.

This study investigated the composition of Tartary buckwheat oil fermented by Monascus purpureus and extracted under supercritical CO2 conditions (FTBO) and evaluated its effects on lipid-lowering, inflammation modulation, and gut microbial regulation in mice that were fed a high-fat diet (MOD). Compared with the raw oil (TBO), the γ-oryzanol content reached 27.09 mg g-1; the monounsaturated fatty acid (MUFA) content (such as oleic acid and palmitic acid) was elevated; and the antioxidant capacities of DPPH, ABTS, and hydroxyl were improved in FTBO (p < 0.0001). Then, supplementation with FTBO had a remarkable effect on reducing the body weight and visceral obesity as well as alleviating hyperglycemia, dyslipidemia, inflammatory reactions, and liver damage. The TC, TG, and LDL-C levels in the liver and plasma were reduced, and the HDL-C levels in the liver were increased (p < 0.05). In particular, the high-dose group (FTBOH) exhibited the most significant effect on reducing the pro-inflammatory cytokines ET, TNF-α, IL-1ß, and IL-6 in the liver, which were 18.85, 570.12, 50.47, and 26.22 pg mL-1, respectively (p < 0.05). Moreover, FTBO reversed intestinal disorders and increased the intestinal microbial diversity and richness. The relative abundance of beneficial bacteria, such as Bifidobacterium, Lactobacillus, Limosilactobacillus, and Lachnospiraceae_UCG-006, were increased, and the relative abundance of the harmful bacteria Staphylococcus and Lachnoclostridium were reduced. In summary, FTBO has potential applications as a dietary supplement or dietary modifier in lowering blood lipids, modulating immune activity, and reversing intestinal disorders. This study provides reference guidance for the subsequent industrialization and development of Tartary buckwheat, the extension of the industrial chain, the development of new products, and the extraction of functional components.

Immune Exosomes Loading Self-Assembled Nanomicelles Traverse the Blood-Brain Barrier for Chemo-immunotherapy against Glioblastoma.

Effective drug delivery and prevention of postoperative recurrence are significant challenges for current glioblastoma (GBM) treatment. Poor drug delivery is mainly due to the presence of the blood-brain barrier (BBB), and postoperative recurrence is primarily due to the resistance of GBM cells to chemotherapeutic drugs and the presence of an immunosuppressive microenvironment. Herein, a biomimetic nanodrug delivery platform based on endogenous exosomes that could efficiently target the brain without targeting modifications and co-deliver pure drug nanomicelles and immune adjuvants for safe and efficient chemo-immunotherapy against GBM is prepared. Inspired by the self-assembly technology of small molecules, tanshinone IIA (TanIIA) and glycyrrhizic acid (GL), which are the inhibitors of signal transducers and activators of transcription 3 from traditional Chinese medicine (TCM), self-assembled to form TanIIA-GL nanomicelles (TGM). Endogenous serum exosomes are selected to coat the pure drug nanomicelles, and the CpG oligonucleotides, agonists of Toll-like receptor 9, are anchored on the exosome membrane to obtain immune exosomes loaded with TCM self-assembled nanomicelles (CpG-EXO/TGM). Our results demonstrate that CpG-EXO/TGM can bind free transferrin in blood, prolong blood circulation, and maintain intact structures when traversing the BBB and targeting GBM cells. In the GBM microenvironment, the strong anti-GBM effect of CpG-EXO/TGM is mainly attributed to two factors: (i) highly efficient uptake by GBM cells and sufficient intracellular release of drugs to induce apoptosis and (ii) stimulation of dendritic cell maturation and induction of tumor-associated macrophages polarization by CpG oligonucleotides to generate anti-GBM immune responses. Further research found that CpG-EXO/TGM can not only produce better efficacy in combination with temozolomide but also prevent a postoperative recurrence.

Bio-fabricated nanodrugs with chemo-immunotherapy to inhibit glioma proliferation and recurrence.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with high mortality. Knowledge of the stemness concept has developed recently, giving rising to a novel hallmark with therapeutic potential that can help in management of GBM recurrence and prognosis. However, limited blood-brain barrier (BBB) penetration, non-discriminatory distribution, and deficiency of diagnosis remain three major obstacles need to be overcome for further facilitating therapeutic effects. Herein, D4F and α-Melittin (a-Mel) are co-assembled to construct bio-fabricated nanoplatforms, which endowed with inherent BBB permeability, precise tumor accumulation, deep penetration, and immune activation. After carrying arsenic trioxide (ATO) and manganese dichloride (MnCl2), these elaborated nanodrugs, Mel-LNPs/MnAs, gather in tumor foci by natural pathways and respond to microenvironment to synchronously release Mn2+ and As3+, achieving real-time navigating-diagnosis and tumor cell proliferation inhibition. Through down regulating CD44 and CD133 expression, the GBM stemness was suppressed to overcome its high recurrence, invasion, and chemoresistance. After being combined with temozolomide (TMZ), the survival rate of GBM-bearing mice is significantly enhanced, and the rate of recurrence is powerfully limited. Collectively, this tumor-specific actuating multi-modality nanotheranostics provide a promising candidate for clinical application with high security.