Injectable thermo-sensitive hydrogel enhances anti-tumor potency of engineered Lactococcus lactis by activating dendritic cells and effective memory T cells

Engineered bacteria have shown great potential in cancer immunotherapy by dynamically releasing therapeutic payloads and inducing sustained antitumor immune response with the crosstalk of immune cells.In previous studies,FOLactis was designed,which could secret an encoded fusion protein of Fms-related tyrosine kinase 3 ligand and co-stimulator OX40 ligand,leading to remarkable tumor suppression and exerting an abscopal effect by intratumoral injection.However,it is difficult for intratumoral administration of FOLactis in solid tumors with firm texture or high internal pressure.For patients without lesions such as abdominal metastatic tumors and orthotopic gastric tumors,intratumoral injection is not feasible and peritumoral maybe a better choice.Herein,an engineered bacteria delivery system is constructed based on in situ temperature-sensitive poloxamer 407 hydrogels.Peritumoral injection of FOLactis/P407 results in a 5-fold increase in the proportion of activated DC cells and a more than 2-fold increase in the proportion of effective memory T cells(TEM),playing the role of artificial lymph island.Besides,administration of FOLactis/P407 significantly inhibits the growth of abdominal metastatic tumors and orthotopic gastric tumors,resulting in an extended survival time.Therefore,these findings demonstrate the delivery approach of engineered bacteria based on in situ hydrogel will promote the efficacy and universality of therapeutics.

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy

Currently the main treatment of acute myeloid leukemia(AML)is chemotherapy combining hematopoietic stem cell transplantation.However,the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice.Thus,there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects.Here,we revealed that umbilical cord-derived mesenchymal stem cells(UC-MSC)efficiently induced AML cell differentiation by shuttling the neutrophil elastase(NE)-packaged extracellular vesicles(EVs)into AML cells.Interestingly,the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor(VDR)activation in UC-MSC.Chemical activation of VDR by using its agonist 1a,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model.Based on these discoveries,to evade the risk of hypercalcemia,we synthetized and identified sw-22,a novel non-steroidal VDR agonist,which exerted a synergistic prodifferentiation function with UC-MSC on mitigating the progress of AML.Collectively,our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

Versatile iron-vitamin K_(3) derivative-based nanoscale coordination polymer augments tumor ferroptotic therapy

Ferroptosis is a newly form of regulated cell death,which has attracted great attention for tumor therapy.Herein,we prepared nanoscale coordination polymer Fe-NQA particles to deliver iron and NQA(vitamin K3 derivative)into tumor cells,which synergistically promoted ferroptotic therapy for inhibiting tumor growth,preventing metastasis,and overcoming radioresistance.

Jug-PLGA-NPs, a New Form of Juglone with Enhanced Efficiency and Reduced Toxicity on Melanoma

Objective: To verrify the anti-tumor efficacy and toxicity between juglone(Jug) and Jug-loaded poly lactic-co-glycolic acid(PLGA) nanoparticles(Jug-PLGA-NPs). Methods: Jug-PLGA-NPs were prepared by ultrasonic emulsification. The anti-tumor activity of Jug(2, 3, 4 μg/mL) and Jug-PLGA-NPs(Jug: 2, 3, 4 μg/mL) in vitro was measured by MTT assay and cell apoptosis analysis. The distribution, anti-tumor effect and biological safety in vivo was evaluated on A375 nude mice. Results: With the advantage of good penetration and targeting properties, Jug-PLGA-NPs significantly inhibited proliferation and migration of melanoma cells both in vitro and in vivo(P<0.05 or P<0.01) with acceptable biocompatibility. Conclusions: Jug can inhibit the growth of melanoma but is highly toxic. With the advantage of sustained release, tumor targeting, anti-tumor activity and acceptable biological safety, Jug-PLGA-NPs provide a new pharmaceutical form for future application of Jug.