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

  • Adv Sci (Weinh). 2026 May 6:e75559. doi: 10.1002/advs.75559.
Yao Xiao  1 ,  Yuxuan Yang  2 ,  Haosen Qiu  2 ,  Jia Yang  3 ,  Hao Liang  1 ,  Zhaojun Jiang  1 ,  Xiao Tong  4 ,  Yongying Li  1  5 ,  Qunfeng Huang  1 ,  Jiaming Wu  6 ,  Tian Lin  2 ,  Jiang Yu  2 ,  Min Liang  1
Affiliations
  • 1. Department of Oncology, Department of Oncology, GuangDong Engineering Technology Research Center of Biological Targeting Diagnosis, Therapy and Rehabilitation, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
  • 2. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 3. Department of General Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
  • 4. Department of Respiratory and Critical Care Medicine, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
  • 5. The Fifth Clinical College of Guangzhou Medical University, Guangzhou, China.
  • 6. Department of Gastrointestinal Surgery, Affiliated Hospital of Jiaxing University, Jiaxing, China.
PMID: 42089455 DOI: 10.1002/advs.75559
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 CA2+ in the acidic tumor microenvironment; and curcumin (CUR) amplifies intracellular calcium overload by promoting endoplasmic reticulum CA2+ 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.

Keywords
PANoptosis; calcium overload; colorectal cancer; immunogenic cell death; immunotherapy.
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