This work is a recent discovery of Dr. Wanwan Li’s group’s continuous research on bismuth-based materials. It is well-known that semimetallic bismuth (Bi) with low biological toxicity has been regarded as the “green element” and its compounds have also been widely used in commercial clinical medicine. For instance, bismuth subnitrate was used to treat dyspepsia in 1786¹ and bismuth subsalicylate has been used to treat Campylobacter infections since 1900². In 2006, Ralph Weissleder et al for the first time demonstrated the benefits of the high-Z feature of Bi (Z=83) for use in computed tomography (CT) imaging³, whereas other groups have demonstrated their potential in photothermal theranostics⁴. In the past few years, our group has also conducted extensive research on theranostic capabilities of Bi⁰ and Bi^III-based nanomaterials^5,6. However, compared to the vast interest in conventional Bi⁰ and Bi^III-based nanomaterials, there has been little research focusing on the features of Bi^V-based nanomaterials, as one can imagine that the high redox potential of Bi^V should behave like other Fenton-like elements that widely used in anticancer field. After searching the literature, we found that the commercially available sodium bismuthate would be a suitable component to construct nanomaterials, however, there has been no proven method to fabricate uniform monodispersed sodium bismuthate nanostructures. Under this circumstance, we proposed the template-assisted method and for the first time achieved uniform monodispersed sodium bismuthate nanostructures, and once we achieved this, the story began.

ROS with evoked immunotherapy holds tremendous promise for cancer treatment

The highly complex tumor immunosuppressive microenvironment of a majority of solid tumors with a low frequency of pro-inflammatory immune cells has greatly restricted the clinical application of immunotherapy⁷. Reactive oxygen species (ROS) can not only directly cause apoptosis and necrosis of cells by damaging lipids, proteins, and DNA at an excessive level but also evoke immune responses by inducing immunogenic cell death (ICD). However, despite various therapeutic techniques including radiotherapy, photodynamic therapy, and so on have been used to modulate ROS generation⁸, the dependence on either exogenous X-rays or lasers and/or endogenous H₂O₂ or O₂ has highly impeded ROS generation efficacy and hindered ROS-based direct removal of tumor burden and ROS-based cancer immunotherapy⁹. Therefore, alternative approaches with less or no dependence on exogenous excitation and endogenous H₂O₂ and O₂ are urgently needed.

Bi(V)-based nanoplatform with spontaneous ROS generation can trigger immune responses

We demonstrated the use of Bi(V)-based nanoplatform can solve this problem (Fig. 2). In brief, upon exposure to the tumor microenvironment, the proposed nanoplatform undergoes continuous H⁺-accelerated hydrolysis with •OH and ¹O₂ generation through electron transfer-mediated Bi^V-to-Bi^III conversion and lattice oxygen transformation, thus allowing efficient anticancer efficacy. At first, we encountered difficulties in the synthesis of Bi(V)-based nanoplatform. We have tried many conventional inorganic nanomaterial preparation methods but could not achieve Bi(V)-based nanoplatform with uniform particle size and ideal size. Coincidentally, Dr. Yizhang Tang noticed an academic poster posted in the Laboratory exhibition area, which showed a template method to prepare nanospheres with uniform particle sizes. Dr. Yizhang Tang was inspired and decisively tried to use bismuth oxide nanospheres as a template to synthesize pentavalent Bi(V) nanoplatform (NaBi^VO₃-PEG) and achieved a uniform porous spherical nanoflower structure (Fig. 3a,b).

After modification with a PEGylated phospholipid outer layer, we demonstrated the yielded NaBi^VO₃-PEG-PEG indeed could generate ROS through H⁺-mediated electron transfer and lattice oxygen migration (Fig. 3c-f). We established three animal models to explore the efficacy of NaBi^VO₃-PEG in cancer treatment. NaBi^VO₃-PEG administrated intratumorally produced strong antitumor efficacy and activated systemic antitumor immune responses against distant tumors and tumor metastasis (Fig. 4a,b). NaBi^VO₃-PEG administrated intravenously could efficiently accumulate and hydrolyze in tumor tissues, which dramatically augmented therapeutic efficiency with alternative real-time CT imaging and on-demand RT capabilities for broader practical scenarios. Interestingly, simply twice intravenous administration of NaBi^VO₃-PEG also exerted robust tumor inhibition (Fig. 4c).

Overall, we reported and disclosed the redox feature of high-valence Bi(V) nanoplatform (Bi^III→Bi^V→Bi^III) for cancer therapy, which has never been reported by previous work focusing on either Bi⁰ or Bi^III-based nanomaterials. Compared to the lack of Bi(V)-based materials or applications in inorganic chemistry, there have been several cases involving Bi(V)-based molecules in organometallic and organic chemistry, thus leaving a huge blank in the field of inorganic chemistry. The successful fabrication of high-valence Bi(V) nanoplatform (NaBi^VO₃-PEG) in this work is achieved by our proposed template-assisted method. Therefore, our work might inspire more designs and use of Bi or Bi(V) in the field of inorganic chemistry and provide a promising paradigm for achieving ROS regardless of either exogenous stimulus or endogenous H₂O₂ and O₂ based on high-valence Bi(V) nanomedicine.

References:

1. Sun H. Biological Chemistry of Arsenic, Antimony and Bismuth, Wiley, Chichester, 2011
2. The Role of Bismuth Subsalicylate S3–S8 published by Oxford Univ. Press, 1990
3. Rabin O, et al. An X-ray computed tomography imaging agent based on long-circulating bismuth sulphide nanoparticles. Nat. Mater. 5, 118–122 (2006)
4. Yu X, et al. Pnictogen semimetal (Sb, Bi)-based nanomaterials for cancer imaging and therapy: a materials perspective. ACS Nano15, 2038–2067 (2021)
5. Yu X, et al. Ultrasmall semimetal nanoparticles of bismuth for dual-modal computed tomography/photoacoustic imaging and synergistic thermoradiotherapy. ACSNano11, 3990–4001 (2017)
6. Li A, et al. Synergistic thermoradiotherapy based on PEGylated Cu3BiS3 ternary semiconductor nanorods with strong absorption in the second near-infrared window. Biomaterials112, 164-175 (2017)
7. Zitvogel L, et al. Immunological off-target effects of imatinib. Nat. Rev. Clin. Oncol.13, 431-446 (2016)
8. Yang B,et al.Reactive oxygen species (ROS)-based nanomedicine. Chem. Rev. 119, 4881-4985 (2019)
9. He M, et al. Reactive oxygen species-powered cancer immunotherapy: Current status and challenges. J. Controlled Release356, 623-648 (2023)

Paper link: DOI : 10.1038/s41467-025-56110-7