Trojan horse strategy using cesium nanosalts shows powerful anti-cancer effects

Recently, a team led by Academician Hongjie Zhang, Researcher Shuyan Song, Associate Researcher Pengpeng Lei, and Dr. Ran An at the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, developed an innovative strategy to construct a series of biodegradable cesium nanosalts. These nanosalts activate anti-tumor immunity by inducing pyroptosis and metabolic intervention. The nanosalts induce ion endocytosis in tumor cells using a Trojan horse strategy, disrupting intracellular ion homeostasis, causing a surge in osmotic pressure, and ultimately triggering pyroptosis. Cesium ions (Cs⁺) can inhibit the ion channel activity of sodium/glucose cotransporters, hindering glucose transport. The introduction of docosahexaenoic acid (DHA) not only amplifies pyroptosis but also initiates immunogenic ferroptosis. The multiple effects of the nanosalts lead to the release of damage-related molecular patterns, thereby activating a robust anti-tumor immune response. The article was published as an open access research article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background information:

Nanosalts, as an important branch of excellent tumor therapeutic agents, deserve full recognition for their value. Nanosalts can bypass ion pumps/channels and enter cells via plasma membrane endocytosis. Due to their high water solubility, nanosalts gradually dissolve and release ions. When these ions accumulate to a certain concentration, they disrupt ion homeostasis. Simultaneously, due to the reverse osmotic gradient formed across the plasma membrane, these ions are trapped inside the cell, leading to a sharp increase in osmotic pressure. The resulting cell lysis is not only a physical process but also involves the pyroptosis-mediated pathway. Cell swelling and cytoplasmic efflux release large amounts of damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines, ultimately triggering a strong inflammatory response that reprograms the immunosuppressive tumor microenvironment, causing its regression. Once recognized by phagocytosis-related receptors, DAMPs can promote antigen presentation, induce widespread immune cell infiltration, and activate anti-tumor immune responses.

However, compared with other nanomaterials, the library of nanosalts is still not rich enough, and many soluble electrolytes have not yet been nanoscaled. Developing novel preparation strategies and expanding the library of nanosalts, especially nanosalts with ion-interference therapeutic functions, is particularly important for addressing the challenges of treating malignant tumors.

Highlights of this article:

In this study, the authors achieved the directed synthesis of cesium-based nanosalts and used cesium bromide nanosalts as a proof-of-concept to conduct research on pyroptosis-based tumor immunotherapy. The main highlights of this work include: 1) the development of a novel method for synthesizing cesium-based nanosalts, allowing for wide-range control of nanosalt size; 2) the nanosalts utilize a "Trojan horse" strategy to overcome ion channel barriers, delivering ions into the cell via endocytosis, inducing a surge in osmotic pressure and triggering pyroptosis, releasing DAMPs, and activating a systemic anti-tumor immune response; 3) Cs⁺ can interfere with the plasma membrane potential, inhibiting glucose uptake by affecting the function of sodium/glucose cotransporters, thereby disrupting tumor metabolic homeostasis; 4) the dietary nutrient DHA not only enhances the pyroptosis effect but also induces immunogenic ferroptosis, forming a dual synergistic therapeutic mechanism; and 5) the anti-tumor immune response of the nanosalts was systematically verified through in vitro and in vivo experiments, demonstrating their significant ability to inhibit tumor invasion and metastasis.

Summary and outlook:

In summary, this work successfully constructed a biodegradable cesium-based nanosalt system, developing a remarkable anti-tumor immunotherapeutic agent. Through liposome encapsulation technology, the pyroptosis inducer DHA was successfully loaded while simultaneously regulating the ion dissolution and release rate, forming a complete therapeutic system. This nanosalt overcomes ion channel limitations, employing a "Trojan horse" strategy to induce ion endocytosis in tumor cells, disrupting intracellular ion homeostasis, triggering an osmotic pressure surge, and leading to pyroptosis. DHA not only enhances the pyroptosis effect but also induces a synergistic effect of ferroptosis. Intracellularly released cesium ions interfere with the function of sodium-glucose cotransporters, inhibiting glucose uptake and thus disrupting metabolic balance. Under the synergistic effect of multiple pathways, a large amount of DAMPs are released, successfully activating the in vivo anti-tumor immune response. On the one hand, it promotes the maturation of lymph node dendritic cells, mediating downstream immune responses by regulating T cell proliferation; on the other hand, it drives a large infiltration of immune cells, effectively inhibiting tumor proliferation and metastasis. This study confirms that nanosalts are highly promising anti-tumor agents, and the development of next-generation nanosalts provides a reliable pathway for efficient tumor treatment.

These results were published as a research article in CCS Chemistry. Academician Hongjie Zhang, Researcher Shuyan Song, Associate Researcher Pengpeng Lei, and Dr. Ran An from Changchun Institute of AppliedChemistry, Chinese Academy of Sciences are the corresponding authors, and Pengye Du is the first author.