Mn<sup>2+</sup>/CpG Oligodeoxynucleotides Codecorated Black Phosphorus Nanosheet Platform for Enhanced Antitumor Potency in Multimodal Therapy
Kai Ling, Jintao Zheng, Xiaohong Jiang, Weijie Huang, Youqing Mai, Chuanghong Liao, Shuting Fan, Jianlan Bu, Rui Li, Bingchun Zeng, Qiunuan Zheng, Ruibin Huang, Zhiyang Li, Nai-Kei Wong, Hongyan Jiang
Abstract
Manganese ions (Mn 2+ )-coordinated nanoparticles have emerged as a promising class of antitumor nanotherapeutics, capable of simultaneously disrupting the immunosuppressive tumor microenvironment (TME) and triggering the stimulator of interferon genes (STING) pathway-dependent antitumor immunity. However, the activation of STING signaling by Mn 2+ -based monotherapies is suboptimal for comprehensive stimulation of antigen presenting cells and reversal of immunosuppression in the TME. Here, we report the design of a Mn 2+ /CpG oligodeoxynucleotides (ODNs) codecorated black phosphorus nanosheet (BPNS@Mn 2+ /CpG) platform based on the Mn 2+ modification of BPNS and subsequent adsorption of synthetic CpG ODNs. The coordination of Mn 2+ significantly improved the stability of BPNS and the adsorption of CpG ODNs. The acidic TME and endosomal compartments can disrupt the Mn 2+ coordination, triggering pH-responsive release of CpG ODNs and Mn 2+ to effectively activate the Toll-like receptor 9 and STING pathways. As a result, M2-type macrophages and immature dendritic cells were strongly stimulated in the TME, thereby increasing T lymphocyte infiltration and reversing the immunosuppression within the TME. Phototherapy and chemodynamic therapy, utilizing the BPNS@Mn 2+ /CpG platform, have demonstrated efficacy in inducing immunogenic cell death upon 808 nm laser irradiation. Importantly, the treatment of BPNS@Mn 2+ /CpG with laser irradiation exhibited significant therapeutic efficacy against the irradiated primary tumor and effectively suppressed the growth of nonirradiated distant tumor. Moreover, it induced a robust immune memory, providing long-lasting protection against tumor recurrence. This study demonstrated the enhanced antitumor potency of BPNS@Mn 2+ /CpG in multimodal therapy, and its proof-of-concept application as a metal ion-modified BPNS material for effective DNA/drug delivery and immunotherapy.