CaCO3-Assisted Preparation of pH-Responsive Immune-Modulating Nanoparticles for Augmented Chemo-Immunotherapy

Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.

A homologous and molecular dual-targeted biomimetic nanocarrier for EGFR-related non-small cell lung cancer therapy

The abnormal activation of epidermal growth factor receptor(EGFR)drives the development of non-small cell lung cancer(NSCLC).The EGFR-targeting tyrosine kinase inhibitor osimertinib is frequently used to clinically treat NSCLC and exhibits marked efficacy in patients with NSCLC who have an EGFR mutation.However,free osimertinib administration exhibits an inadequate response in vivo,with only~3%patients demonstrating a complete clinical response.Consequently,we designed a biomimetic nanoparticle(CMNP^(@Osi))comprising a polymeric nanoparticle core and tumor cell-derived membrane-coated shell that combines membrane-mediated homologous and molecular targeting for targeted drug delivery,thereby supporting a dual-target strategy for enhancing osimertinib efficacy.After intravenous injection,CMNP^(@Osi)accumulates at tumor sites and displays enhanced uptake into cancer cells based on homologous targeting.Osimertinib is subsequently released into the cytoplasm,where it suppresses the phosphorylation of upstream EGFR and the downstream AKT signaling pathway and inhibits the proliferation of NSCLC cells.Thus,this dual-targeting strategy using a biomimetic nanocarrier can enhance molecular-targeted drug delivery and improve clinical efficacy.

Nanoparticles(NPs)-mediated systemic mRNA delivery to reverse trastuzumab resistance for effective breast cancer therapy

Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy.The first monoclonal antibody authorized for treating human epidermal growth receptor 2(HER2)-positive breast cancer is trastuzumab.However,resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes.To address this issue,tumor microenvironment(TME)pH-responsive nanoparticles(NPs)were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer(BCa).This nanoplatform is comprised of a methoxyl-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)copolymer with a TME pH-liable linker(Meo-PEG-Dlinkm-PLGA)and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction.When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously,they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface.With the intracellular mRNA release to up-regulate PTEN expression,the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells,thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.

Simultaneous elimination of cancer stem cells and bulk cancer cells by cationic-lipid-assisted nanoparticles for cancer therapy

有说服力的证据显示在恶意的肿瘤以内的癌症干细胞(CSC ) 的存在为化疗的失败主要负责。因此而不是仅仅指向体积癌症房间， CSC 和体积癌症房间的同时的消除是必要的改进治疗学的结果。此处，我们设计了 cationic-lipid-assisted nanoparticles DTXL NP 为常规化学疗法的 agentdocetaxel (DTXL ) 和指向 BMI-1 (siBMI-1 ) 的小介入 RNA (siRNA ) 的同时的封装的 siRNA 。我们证实了那 nanoparticles DTX LNP siBMI-1 有效地交付两个治疗学的代理人进 CSC 和体积癌症房间。体积癌症房间被在 DTX LNP siBMI-1 。在胸 CSC， BMI-1 表示是显著地由 DTX LNP siBMI-1 ；因而， stemness 被减少，到 DTXL 的 CSC 的 chemosensitivity 被提高，导致 CSC 的消除。因此，经由 DTX LNP siBMI-1 , siBMI-1 和 DTXL 的联合完全禁止了肿瘤生长并且由在一个 MDA-MB-231 orthotropic 肿瘤的一个鼠科的模型 CSC 和体积癌症房间杀死的 synergistic 阻止了恶化。

Erratum on “Engineering of a universal polymeric nanoparticle platform to optimize the PEG density for photodynamic therapy” [Sci. China. Chem., 2019, 62: 1379–1386]

In a recent publication [1], these images in Figures 6(b, c)(^NPEG-NPCe6 group), S7, S9 and S10 were inadvertently taken the incorrect images in the production. The corrected versions are shown below. And, the quantification of Ce6 fluorescence(as performed in Figure 6(c)) was also corrected(Figure S12).

Engineering of a universal polymeric nanoparticle platform to optimize the PEG density for photodynamic therapy

Nanocarrier-mediated photodynamic therapy(PDT)has attracted extensive attention due to its locoregional therapeutic effect,minimal toxicity to normal tissues,and activation of immune system capability.However,it is still unclear how the physicochemical properties of nanocarriers affect their PDT therapeutic efficacies,which could be very different from those for chemotherapy.Herein,to demonstrate the effect of PEG density on PDT efficacy,we synthesized a series of random polyphosphoesters(PPEs)with different PEG contents by regulating the molar ratios of these monomers,and then these PPEs were used to prepare chlorin e6(Ce6)-loaded polymeric nanoparticles with tunable PEG density.Thereafter,the PDT efficacies of these nanoparticles were carefully and comprehensively evaluated.We demonstrate that the moderate PEG density(3.01 PEG/nm^2)of nanocarrier exhibited the best PDT therapeutic efficacy in a mouse model of pancreatic cancer due to its efficient balance of prolonged circulation and tumor cellular uptake.