On July 6, 2025, Özcanet et al. from the Biofunctional Nanomaterials Design (BIND) Laboratory at Bogazici University published their latest research findings in ACS Applied Polymer Materials, entitled "Hyaluronic acid nanocapsules as pH-responsive nanocarriers for controlled doxorubicin delivery". This work successfully engineers a highly stable, hollow nanocapsule platform utilizing hyaluronic acid (HA), a crucial Glycan. Their main finding demonstrates that these nanocapsules achieve significantly enhanced, localized release of the chemotherapy agent doxorubicin (DOX) specifically in the slightly acidic environment characteristic of solid tumors, thereby promising a major step forward in minimizing systemic toxicity.

Overview

The core impetus for this research stems from the ongoing need for safer and more effective cancer treatments. Conventional chemotherapy is hampered by a lack of selectivity, leading to collateral damage in healthy tissues. Glycans like HA naturally possess high biocompatibility and specific biological recognition capabilities. HA's biological role is particularly relevant in oncology due to its affinity for the CD44 receptor, which is frequently overexpressed on the surface of various cancer cells. This natural biological targeting, combined with the active environmental targeting (pH-responsiveness) achieved by the hyaluronic acid nanocapsules (HANCs) design, makes the system a powerful dual-targeting strategy—a crucial advancement in next-generation nanomedicine design.

Fig.1 Schematic overview of this study, including synthesis of drug-loaded HANCs, in vitro drug release, and cytotoxicity assessment. (Özcan, et al., 2025)

Research Results

• Precision Synthesis of Uniform Glycan Nanocapsule Morphology

The team employed a polyaddition reaction within an inverse miniemulsion technique to synthesize the HANCs. This method is critical because it allows for the precise control of the interfacial reaction between isocyanate groups and the hydroxyl groups of HA. Using transmission electron microscopy (TEM), they confirmed the resulting structure was a hollow capsule morphology, not merely a solid nanoparticle. This hollow structure is innovative as it maximizes the drug loading capacity within the interior aqueous core while the HA acts as a protective, functional shell. This degree of structural control is essential for nanomedicines intended for predictable in vivo circulation.

• Robust Colloidal Stability for Prolonged Circulation

The researchers meticulously optimized their formulation to achieve exceptional structural integrity. Through long-term stability monitoring of size, polydispersity index (PDI), and zeta potential, the optimized HANC formulation was shown to remain stable and non-aggregating for over 100 days. This remarkable stability—attributable to the robust shell cross-linked via polyaddition—is a prerequisite for effective intravenous administration, ensuring the nanocarriers persist long enough to reach the target site without premature clearance by the mononuclear phagocyte system.

Fig.2 Stability of HANC4 formulation: Size, PDI (A), and zeta potential (B). (Özcan, et al., 2025)

• Targeted Release via Acid-Sensing Glycan Hydrogel Swelling

The defining functional success of the HANCs is their pH-responsive release mechanism. The glycan, HA, possesses numerous carboxylic acid groups. When exposed to the slightly acidic pH (pH 6.5) mimicking the tumor microenvironment, these groups become partially protonated. This change disrupts the internal electrostatic repulsions and alters the hydration and swelling behavior of the HA polymer network. The study confirmed that the HANCs exhibited a significantly higher and rapid release of DOX at pH 6.5, while drug leakage at neutral pH (7.4, healthy tissue) was severely limited. This targeted, on-demand drug activation represents a highly selective mechanism, mitigating the severe side effects associated with widespread systemic distribution of potent chemotherapy agents.

Conclusion

The successful Synthesis of stable, hollow HANC with defined pH-responsive drug release kinetics establishes a highly practical and scalable nanocarrier platform. The team's innovation lies in leveraging the intrinsic chemical structure of the HA glycan—its charged functional groups—to develop an environmentally sensitive "smart" delivery system. Beyond the immediate application in oncology, the robust engineering principles demonstrated here hold immense potential for my field of marine glycobiology. The control over hydrogel swelling and stability could be directly applied to creating bio-responsive delivery systems for controlled release of active agents in the marine environment, such as localized delivery of environmentally safe compounds to control invasive species or biofouling, underscoring the universal applicability of sophisticated glycan engineering.