Tunable ion-release biodegradable nanoparticles enhanced pyroptosis for tumor immunotherapy

Pyroptosis is an effective strategy for inducing inflammatory responses in 'cold' tumors, boosting the efficacy of immunotherapy. Although biodegradable inorganic nanoparticles (BINPs) show great potential in pyroptosis by releasing ions to break intracellular homeostasis, the limited intracellular ion release efficiency restricts pyroptosis level and subsequent immune activation. Herein, by heterovalent substitution strategy, a series of Na₃ZrF₇:x%Yb³⁺ (NZF:x%Yb, x = 0, 9, and 18) BINPs with tunable intracellular ion release efficiency are synthesized for enhanced pyroptosis and tumor immunotherapy. Specifically, the size of NZF:x%Yb³⁺ gradually decrease with increasing Yb³⁺ -doped and smaller NZF:x%Yb presents a higher degradation rate and cellular uptake ability, enabling improved intracellular ion release efficiency. This leads to drastic intracellular homeostasis stress and abundant ROS generation, thereby provoking enhanced caspase-1-related pyroptosis. Antitumor experiments in triple-negative breast cancer model confirm that the ultra-small NZF:x%Yb (NZF:18%Yb) with the highest intracellular ion release efficiency shown the most effective antitumor ability, and significant inhibition of distal tumor. This study reveals precise control over the size of NZF:x%Yb is especially vital to achieving pyroptosis-induced immunotherapy, which offers a new perspective for the design of BINPs.