While erastin is a potent ferroptosis inducer (system xc⁻ inhibitor), its clinical use is hampered by poor solubility and off-target toxicity. We developed ECINs, a CD44-targeted, laser-activatable nanomedicine using chondroitin sulfate A (CSA) and propanesulfonate indocyanine green (psICG) to encapsulate erastin. CSA ensures precise targeting to CD44-overexpressing hepatocellular carcinoma (HCC) cells. psICG provides dual-functionality: without laser, it acts as a ROS scavenger, suppressing off-target toxicity and widening the therapeutic index; upon 808 nm NIR irradiation, it generates hyperthermia and singlet oxygen for selective chemo-phototherapy. ECINs showed 186.7 ± 1.1 nm size and 93.0 ± 0.8% encapsulation efficiency. Unlike free erastin inducing canonical ferroptosis (lipid ROS/GSH depletion), ECINs triggered G1-phase cell cycle arrest without significant ferroptotic features. Upon laser activation, the IC₅₀ markedly dropped from 13.0 μg/mL to 0.60 μg/mL, demonstrating pronounced chemo-phototherapeutic enhancement. In SK-HEP-1 xenograft mice, ECINs showed 1.9-fold higher tumor accumulation while reducing lung and spleen distribution by 203-fold and 19.1-fold, respectively. Laser-treated ECINs achieved a 2.6-fold tumor volume reduction versus free erastin with minimal toxicity. Thus, the ECINs platform offers a promising HCC therapy by balancing potent efficacy with inherent off-target safety.