<p>The Hyaluronic Acid-Poly (ethylene glycol)-Poly(ε-caprolactone) (HA-PEG-PCL) amphiphilic triblock copolymers function as multifunctional nanocarriers which deliver cancer treatment through their active targeting capacity and prolonged bloodstream presence and ability to release drugs upon specific stimulus detection. The review examines how HA-PEG-PCL system structures link to their properties and performance from copolymer production through physicochemical features and self-assembly behavior to therapeutic performance assessment. HA-PEG-PCL copolymers form micellar nanoparticles which range from 50 to 200 nanometers in size and maintain stability during systemic circulation through their low critical micelle concentrations which range from 10⁻⁵ to 10⁻⁷ M. The experimental studies demonstrate that the drug loading efficiencies reach between 70 and 90% which surpasses the efficiency of most traditional polymeric carriers. The presence of hyaluronic acid enables CD44 active targeting which results in CD44-overexpressing cancer cells absorbing 2 to 4 times more than non-targeted systems. The in vivo studies show that tumor accumulation increases approximately three times while enhancing therapeutic efficacy when compared to free medicines. The HA-PEG-PCL nanocarriers show 2 to 5 times lower IC₅₀ values for doxorubicin and paclitaxel which demonstrates their improved ability to transport drugs into cells and kill cancer cells. The copolymer structure permits multiple stimuli detection at pH levels below 7 and redox reactions and high temperatures which enables controlled drug release in tumor microenvironments. The preclinical results show promise but the research faces challenges because the technology needs to develop methods for scalable synthesis and catalyst-free production and regulatory approval processes. The HA-PEG-PCL triblock copolymers function as a flexible platform which scientists can adapt to create new targeted nanomedicine and multimodal cancer treatments.</p> Graphical Abstract <p></p>