Mn2+/CpG Oligodeoxynucleotides Codecorated Black Phosphorus Nanosheet Platform for Enhanced Antitumor Potency in Multimodal Therapy.

Manganese ions (Mn2+)-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 Mn2+-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 Mn2+/CpG oligodeoxynucleotides (ODNs) codecorated black phosphorus nanosheet (BPNS@Mn2+/CpG) platform based on the Mn2+ modification of BPNS and subsequent adsorption of synthetic CpG ODNs. The coordination of Mn2+ significantly improved the stability of BPNS and the adsorption of CpG ODNs. The acidic TME and endosomal compartments can disrupt the Mn2+ coordination, triggering pH-responsive release of CpG ODNs and Mn2+ 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@Mn2+/CpG platform, have demonstrated efficacy in inducing immunogenic cell death upon 808 nm laser irradiation. Importantly, the treatment of BPNS@Mn2+/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@Mn2+/CpG in multimodal therapy, and its proof-of-concept application as a metal ion-modified BPNS material for effective DNA/drug delivery and immunotherapy.

Mn2+ modified black phosphorus nanosheets with enhanced DNA adsorption and affinity for robust sensing.

To develop various biosensors, several 2D nanomaterials adsorb DNA probes (aptamers) via π-π stacking interactions. However, interference from DNA displacement by external non-targeted ligands has precluded their practical applications for specific detection and imaging at high protein concentrations. Metal coordination is an attractive strategy for biomolecular crosslinking and functional molecular self-assembly. Herein, a robust 2D biosensor nanoplatform was developed to enhance DNA adsorption and affinity using Mn2+-modified black phosphorus nanosheets (BPNS@Mn2+) via metal coordination. The Mn2+ can simultaneously coordinate with the lone pair electrons (π bonds) of the BPNS and nucleotide bases to provide binding sites for DNA nucleobases on the BPNS surface, which greatly enhances the stability of the inner BPNS and improves DNA adsorption and affinity. The DNA adsorption mechanism of BPNS@Mn2+ was also characterized, and is extensively discussed. Without any further modification, this BPNS@Mn2+/DNA biosensor specifically detected single-stranded DNA (linear range: 10-200 nM, detection limit: 5.76 nM) and thrombin (linear range: 20-180 nM, detection limit: 2.39 nM) in 100 nM bovine serum albumin solution. The nonspecific ligands in the environment did not affect the detection performance of the robust biosensor. In addition, the expression levels of microRNA-21 can be imaged and analyzed in living cells using this biosensor, which is consistent with the results of the polymerase chain reaction. This study highlights the potential of metal coordination in surface modification and provides new opportunities for biomedical applications of 2D nanomaterials with superior DNA-adsorption capacity, facilitating the development of biosensor design and nucleic acid/drug delivery.