Manipulating Redox Homeostasis of Cancer Stem Cells Overcome Chemotherapeutic Resistance through Photoactivatable Biomimetic Nanodiscs

Abstract Tumor heterogeneity remains a significant obstacle in cancer therapy due to diverse cells with varying treatment responses. Cancer stem‐like cells (CSCs) contribute significantly to intratumor heterogeneity, characterized by high tumorigenicity and chemoresistance. CSCs reside in the depth of the tumor, possessing low reactive oxygen species (ROS) levels and robust antioxidant defense systems to maintain self‐renewal and stemness. A nanotherapeutic strategy is developed using tumor‐penetrating peptide iRGD‐modified high‐density lipoprotein (HDL)‐mimetic nanodiscs (IPCND) that ingeniously loaded with pyropheophorbide‐a (Ppa), bis (2‐hydroxyethyl) disulfide (S‐S), and camptothecin (CPT) by synthesizing two amphiphilic drug‐conjugated sphingomyelin derivatives. Photoactivatable Ppa can generate massive ROS which as intracellular signaling molecules effectively shut down self‐renewal and trigger differentiation of the CSCs, while S‐S is utilized to deplete GSH and sustainably imbalance redox homeostasis by reducing ROS clearance. Simultaneously, the depletion of GSH is accompanied by the release of CPT, which leads to subsequent cell death. This dual strategy successfully disturbed the redox equilibrium of CSCs, prompting their differentiation and boosting the ability of CPT to kill CSCs upon laser irradiation. Additionally, it demonstrated a synergistic anti‐cancer effect by concurrently eliminating therapeutically resistant CSCs and bulk tumor cells, effectively suppressing tumor growth in CSC‐enriched heterogeneous colon tumor mouse models.