Xia Jiaxuan, Chen Xing, Dong Meichen, Liu Shengyao, Zhang Longlong, Pan Junjie, Wang Jianxin
Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, 201203, China.
Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Biomaterials. 2025 May;316:122998. doi: 10.1016/j.biomaterials.2024.122998. Epub 2024 Dec 9.
Cancer vaccines show promise by eliciting tumor-specific cytotoxic T lymphocytes (CTL) responses. Efficient cytosolic co-delivery of antigens and adjuvants to dendritic cells (DCs) is crucial for vaccines to induce anti-tumor immunity. However, peptide- or nucleic acid-based biomolecules like tumor antigens and STING agonist cyclic-di-GMP (cdGMP) are prone to endosomal degradation, resulting in low cytosolic delivery and CTL response rates. Cationic nanocarriers can improve cytosolic delivery, but their positive charges induce off-target effects. Here, we develop cationic poly(ester amide) based nanoparticles co-loaded with antigens and adjuvant cdGMP (NP(cG, OVA)) for efficient cytosolic delivery and swallow them within antigen self-presenting DCs-derived dendrosomes (ODs) for lymph nodes (LNs) homing. The constructed dendrosomes swallowing nanovaccines ODs/NP(cG, OVA) demonstrated significantly reduced liver accumulation and enhanced LNs and DCs targeting compared to NP(cG, OVA). ODs/NP(cG, OVA) effectively cross-dressed the antigen epitopes on the shell to DCs and facilitated internalization of NP(cG, OVA), realizing DCs cytosolic co-delivery of antigens and adjuvants, thereby promoting antigen presentation, maturation and inflammatory cytokines secretion of DCs. Consequently, DCs stimulated by ODs/NP(cG, OVA) effectively induced activation, proliferation, and differentiation of antigen-specific CTLs that provided robust immune protection against tumor invasion. This work presents a powerful vaccine strategy for cancer immunotherapy.
癌症疫苗通过引发肿瘤特异性细胞毒性T淋巴细胞（CTL）反应展现出前景。将抗原和佐剂高效地共递送至树突状细胞（DC）的胞质溶胶中对于疫苗诱导抗肿瘤免疫至关重要。然而，基于肽或核酸的生物分子，如肿瘤抗原和STING激动剂环二鸟苷酸（cdGMP），容易在内体中降解，导致胞质溶胶递送率和CTL反应率较低。阳离子纳米载体可以改善胞质溶胶递送，但它们的正电荷会引发脱靶效应。在此，我们开发了一种基于阳离子聚（酯酰胺）的纳米颗粒，其共负载了抗原和佐剂cdGMP（NP(cG,OVA)），用于高效的胞质溶胶递送，并将它们包裹在抗原自呈递DC衍生的树突体（OD）中，以便归巢至淋巴结（LN）。与NP(cG,OVA)相比，构建的包裹纳米疫苗的树突体ODs/NP(cG,OVA)显示出肝脏蓄积显著减少，且对LN和DC的靶向性增强。ODs/NP(cG,OVA)有效地将外壳上的抗原表位交叉呈递给DC，并促进了NP(cG,OVA)的内化，实现了DC对抗原和佐剂的胞质溶胶共递送，从而促进了DC的抗原呈递、成熟和炎性细胞因子分泌。因此，由ODs/NP(cG,OVA)刺激的DC有效地诱导了抗原特异性CTL的激活、增殖和分化，为抵抗肿瘤侵袭提供了强大的免疫保护。这项工作为癌症免疫治疗提出了一种强有力的疫苗策略。
