CD44‐Targeting Hydroxyapatite Nanoparticles (HAP) Induce Mitochondrial Dysfunction‐Driven PANoptosis and Immunogenic Cell Death (ICD) via Ca Overload in Colorectal Cancer

ABSTRACT Colorectal cancer (CRC) remains therapeutically challenging due to high metastasis, recurrence, and immunotherapy resistance driven by tumor microenvironment‐mediated immune evasion. Immunogenic cell death (ICD) offers a promising strategy to reshape the immune microenvironment, yet existing ICD inducers suffer from poor targeting efficiency and insufficient death signal release. Here, we constructed a calcium overload‐based smart nanosystem, HA‐HAP@CUR, to achieve highly efficient ICD induction via a triple‐effect mechanism: hyaluronic acid (HA)‐mediated CD44 targeting enables tumor‐selective accumulation; pH‐responsive hydroxyapatite (HAP) degradation releases Ca 2+ in the acidic tumor microenvironment; and curcumin (CUR) amplifies intracellular calcium overload by promoting endoplasmic reticulum Ca 2+ release, collectively establishing a positive feedback loop disrupting calcium homeostasis. Mechanistically, calcium overload induces mitochondrial membrane potential dissipation and sustained mPTP opening, triggering mitochondrial oxidative stress and energy metabolic disorders. This mitochondrial crisis concurrently activates caspase‐3, GSDMD, and RIPK1, synergistically initiating apoptosis, pyroptosis, and necroptosis, ultimately converging into PANoptosis with potent immunostimulatory potential. This strategy, encompassing targeted accumulation, calcium storm activation, and multi‐modal cell death synergy, provides a biologically precise approach to overcoming immunotherapy resistance in CRC.