Chen Xing, Ling Xiang, Xia Jiaxuan, Zhu Ying, Zhang Longlong, He Yuwei, Wang Anni, Gu Guolong, Yin Bo, Wang Jianxin
Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, China.
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, State Key Laboratory of Natural Medicines, Nanjing, 210009, China.
Bioact Mater. 2021 Dec 21;15:15-28. doi: 10.1016/j.bioactmat.2021.12.020. eCollection 2022 Sep.
The cytomembrane-derived delivery platform represents a promising biomimetic strategy in oncotherapy. To achieve durable and reliable tumor inhibition, mature dendrosomes (mDs), which were isolated from bone marrow-derived dendritic cells undergoing CT26 tumor antigen (TA) stimulation, were fused with redox-responsive nanoparticles (NPs) that were composed of poly(disulfide ester amide) polymers with an intensified disulfide density and hydrophobic oxaliplatin (OXA) prodrugs with the ability to potentiate immunogenicity. and results revealed that NP/mDs could induce tumor cell death through mitochondrial pathway and thus created immunogenic microenvironments, but also elicited immunocyte differentiation by TA cross-dressing and infiltration by direct presentation. By further neutralizing immune-regulatory interaction, the administration of PD-L1 antibody (αPD-L1) greatly improved antitumor efficiency of NP/mDs. Furthermore, the effectors of host immune systems effectively inhibited the growth and metastasis of distal tumors, likely because the autologous TA evoked by OXA and allogeneic TA delivered by mDs acted as additional stimuli to reinforce the immune response of tumor-specific T cells and immunosurveillance toward oncogenesis. These results demonstrated that NP/mDs could simultaneously realize immunogenic chemotherapeutics and specific TA delivery. In combination with αPD-L1, the antitumor effect was further enhanced. Therefore, NP/mDs provide a promising strategy for the comprehensive treatment of malignancy.
细胞膜衍生的递送平台是肿瘤治疗中一种很有前景的仿生策略。为了实现持久且可靠的肿瘤抑制,从经CT26肿瘤抗原(TA)刺激的骨髓来源树突状细胞中分离出的成熟树突体(mDs),与由具有增强二硫键密度的聚(二硫代酯酰胺)聚合物和具有增强免疫原性能力的疏水性奥沙利铂(OXA)前药组成的氧化还原响应纳米颗粒(NPs)融合。结果表明,NP/mDs不仅可以通过线粒体途径诱导肿瘤细胞死亡,从而创造免疫原性微环境,还可以通过TA交叉呈递引发免疫细胞分化并通过直接呈递促进浸润。通过进一步中和免疫调节相互作用,给予PD-L1抗体(αPD-L1)大大提高了NP/mDs的抗肿瘤效率。此外,宿主免疫系统的效应器有效抑制了远端肿瘤的生长和转移,这可能是因为OXA引发的自体TA和mDs递送的异体TA作为额外刺激,增强了肿瘤特异性T细胞的免疫反应和对肿瘤发生的免疫监视。这些结果表明,NP/mDs可以同时实现免疫原性化疗和特异性TA递送。与αPD-L1联合使用时,抗肿瘤效果进一步增强。因此,NP/mDs为恶性肿瘤的综合治疗提供了一种很有前景的策略。
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