MnO₂ Nanoflowers Induce Immunogenic Cell Death under Nutrient Deprivation: Enabling an Orchestrated Cancer Starvation‐Immunotherapy

Abstract

MnO2 nanoparticles have been widely employed in cancer immunotherapy, playing a subsidiary role in assisting immunostimulatory drugs by improving their pharmacokinetics and/or creating a favorable microenvironment. Here, the stereotype of the subsidiary role of MnO2 nanoparticles in cancer immunotherapy is challenged. This study unravels an intrinsic immunomodulatory property of MnO2 nanoparticles as a unique nutrient‐responsive immunogenic cell death (ICD) inducer, capable of directly modulating immunosurveillance toward tumor cells. MnO2 nanoflowers (MNFs) constructed via a one pot self‐assembly approach selectively induce ICD to nutrient‐deprived but not nutrient‐replete cancer cells, which is confirmed by the upregulated damage associated molecular patterns in vitro and a prophylactic vaccination in vivo. The underlying mechanism of the MNFs‐mediated selective ICD induction is likely associated with the concurrently upregulated oxidative stress and autophagy. Built on their unique immunomodulatory properties, an innovative nanomaterials orchestrated cancer starvation‐immunotherapy is successfully developed, which is realized by the in situ vaccination with MNFs and vascular disrupting agents that cut off intratumoral nutrient supply, eliciting potent efficacy for suppressing local and distant tumors. These findings open up a new avenue toward biomedical applications of MnO2 materials, enabling an innovative therapeutics paradigm with great clinical significance.

Oral Nanomotor‐Enabled Mucus Traverse and Tumor Penetration for Targeted Chemo‐Sono‐Immunotherapy against Colon Cancer

“…MnO x is known to be degraded into Mn 2+ in the TME with the acidic environment, and the released Mn 2+ can mediate the Fentonlike chemodynamic reaction. [15,25,26] As expected, the viability of NM-treated (5 µg mL −1 ) cells decreased to 55.3% after co-incubation for 24 h (Figure 3a). In the meanwhile, free ID-treated cells also displayed a slight decrease in their viabilities, indicating the weak anti-tumor capacity of free ID molecules.…”

“…The valence states of Mn in MnO x were in good agreement with previous reports. [ 15,25,26 ] Moreover, CS‐ID@NMs displayed a strong peak at binding energy 400.5 eV (N1s), which was distinguishable from the XPS spectrum of MnO x (Figure 1g), suggesting the presence of RSF on their surface.…”

In-Situ Assembly of Janus Nanoprobe for Cancer Activated NIR-II Photoacoustic Imaging and Enhanced Photodynamic Therapy

“…To evaluate the in vitro aggregation ability of MnO 2 –AuNR-Ppa, we simulated the TME to induce nanoprobes aggregation by adding GSH. − Figure A shows that the aggregation was triggered by the degradation of the MnO 2 shell on the surface of MnO 2 –AuNR-Ppa with GSH. After 30 min, the aggregates increased significantly and particle size became larger (Figure B).…”

Metal‐Cyclic Dinucleotide Nanomodulator‐Stimulated STING Signaling for Strengthened Radioimmunotherapy of Large Tumor

“…[ 13 ] Among them, Mn 2+ has attracted growing attention in cancer therapy due to its diverse and intriguing functions, such as antagonizing hypoxia in TME by catalyzing the decomposition of hydrogen peroxide to oxygen, [ 14 ] enhancing T1‐weighted magnetic resonance imaging (MRI) as a T1 contrast agent [ 15 ] and stimulating anti‐tumor immune cells (i.e., macrophages, CD8+ T cells, and natural killer (NK) cells). [ 16 ] In particular, Mn 2+ can increase the sensitivity of cGAS to dsDNA and the binding affinity of cGAMP‐STING and produce the type I IFNs to enhance anti‐tumor immunity. [ 17 ] Therefore, the addition of Mn 2+ to a combined paradigm holds tremendous potential for improving or reviving the antitumor effect in malignant cancer therapy.…”