A programmed sequential organelle-targeted nanoattack strategy for cGAS-STING hyperactivation and potentiated systemic cancer immunotherapy

Abstract

Cancer immunotherapy is hindered by insufficient immunogenic cell death (ICD) and suboptimal cGAS-STING activation. While organelle-targeted therapies hold promise, conventional treatments often fail because single-target attacks are neutralized by tumor buffering networks, whereas simultaneous stress triggers non-immunogenic necrosis. To overcome these issues, a mitochondria-targeting triphenylphosphonium-modified calcium phosphate (TPP-CaP) and an endoplasmic reticulum (ER) stressor thapsigargin (Tg) were encapsulated within a tumor microenvironment (TME)-responsive hollow mesoporous manganese dioxide nanoparticle (HMMDN). The resulting yolk-shell nanoreactor TPP-CaP@Tg@HMMDN was engineered to achieve a programmed sequential organelle-targeted nanoattack. Following endocytosis of tumor cells, the HMMDN shell degrades, disrupting lysosomes to release Mn 2+ and Tg. SERCA pumps are inhibited by Tg to provoke severe ER stress and endogenous Ca 2+ leakage, which forces mitochondria into an overloaded buffering state. Subsequently, these pre-sensitized mitochondria are actively targeted by the later released TPP-CaP, leading to an exogenous Ca 2+ storm, which irrevocably overwhelms the cellular Ca 2+ buffering capacity, precipitating catastrophic mitochondrial collapse. Consequently, ICD is elicited by the massive extrusion of damage-associated molecular patterns. Meanwhile, released mitochondrial DNA synergizes with Mn 2+ to hyperactivate cGAS-STING. In vivo evaluations demonstrate that dendritic cell maturation and CD8 + T cell infiltration are efficiently stimulated, which boosts systemic immunologic response. This paradigm provides an effective methodology to manipulate inter-organelle crosstalk for potentiated cancer immunotherapy.