The core problem the review addresses is deceptively simple. Photothermal therapy, or PTT, uses photothermal agents that absorb near-infrared light and convert it into localized heat, cooking malignant cells while sparing healthy tissue. It sounds elegant, and in many ways it is. But when deployed alone, PTT rarely achieves complete tumor eradication. Light penetrates deep tissues poorly, heat distributes unevenly within tumors, and surviving cancer cells often respond by ramping up heat shock proteins that help them endure future thermal assaults. The result is incomplete ablation, recurrence, and sometimes distant metastasis. The review argues that the solution is not a better heat source but a smarter delivery vehicle, one that combines photothermal killing with chemotherapy, photodynamic therapy, gene therapy, immunotherapy, or radiotherapy in a single nanoscale package.

What makes chitosan and hyaluronic acid such compelling candidates is that they are not synthetic curiosities but molecules the body already knows. Chitosan, derived from the deacetylation of chitin, carries positively charged amino groups that give it a unique combination of biocompatibility, biodegradability, and non-toxicity. These same functional groups make it extraordinarily amenable to chemical modification, allowing researchers to build nanoparticles, hydrogels, and three-dimensional scaffolds tailored to specific therapeutic needs. Hyaluronic acid, a natural mucopolysaccharide and major component of the extracellular matrix, brings a different superpower to the table: an intrinsic affinity for CD44 receptors, which are overexpressed on many cancer cells. This means HA-coated nanoparticles can actively home in on tumors rather than relying solely on passive accumulation through the enhanced permeability and retention effect.

The review details how these two polymers function as complementary design philosophies rather than competing alternatives. Chitosan acts as a chemically versatile engineering matrix, stabilizing photothermal agents such as gold nanoparticles, graphene quantum dots, MXenes, polydopamine, and Prussian blue while preventing their aggregation and improving biocompatibility. Its cationic nature also facilitates endosomal escape through the proton-sponge effect, enhancing cytosolic drug delivery once nanoparticles are inside cancer cells. Hyaluronic acid, by contrast, serves as the biologically active targeting component, directing nanocarriers toward receptor-positive tumor cells through receptor-mediated endocytosis. When combined, as in hybrid chitosan-hyaluronic acid nanoparticles, the two polymers create multicomponent systems that leverage electrostatic interactions between chitosan’s positive amino groups and HA’s negative carboxyl groups to form stable, multifunctional architectures.

Perhaps the most striking aspect of these platforms is their capacity for stimulus-responsive drug release. Rather than dumping their therapeutic payload indiscriminately, these nanosystems are engineered to respond to specific internal and external triggers. The acidic tumor microenvironment, with a pH of approximately 6.5 compared to the physiological 7.4, protonates chitosan’s amino groups, causing the matrix to swell and release its cargo. Acid-labile linkers such as hydrazone and acylhydrazone bonds cleave selectively in the tumor’s acidic conditions, while disulfide bonds are severed by the high intracellular glutathione concentrations found inside cancer cells. External near-infrared irradiation provides temporal control, heating the nanoparticles and accelerating drug release precisely when and where treatment is needed. Some systems go further, incorporating reactive oxygen species-responsive thioketal linkers or enzyme-cleavable peptide sequences that respond to matrix metalloproteinases secreted by tumor cells.

The quantitative performance data compiled in the review illustrate just how far these systems have progressed. In one study, hyaluronic acid-modified gold nanorings loaded with doxorubicin achieved approximately 50 percent drug release at pH 5.0 within eight hours, compared to only about 20 percent at physiological pH, with near-infrared II irradiation further accelerating release. In a pancreatic cancer mouse model, these nanorings achieved a tumor accumulation efficiency of 11.3 percent, roughly threefold higher than unmodified gold nanorods. Another hybrid system combining hyaluronic acid, chitosan, and PLGA nanoparticles loaded with doxorubicin and indocyanine green demonstrated a 2.3-fold increase in cellular uptake in triple-negative breast cancer cells compared to unmodified PLGA nanoparticles, with combined treatment reducing cell viability to 13.5 percent at 48 hours.

Beyond drug delivery, these platforms are increasingly integrating diagnostic imaging capabilities, giving rise to true theranostic systems. Fluorescence imaging using dyes such as DiR or the intrinsic fluorescence of doxorubicin enables real-time visualization of cellular uptake and intracellular release. Photoacoustic imaging and magnetic resonance imaging provide deeper anatomical context, with some platforms incorporating superparamagnetic iron oxide nanoparticles or chelated manganese and gadolinium ions as contrast agents. The review highlights a phototheranostic nanocomplex combining low-molecular-weight hyaluronic acid with chitosan oligosaccharide lactate and a zwitterionic near-infrared dye, which showed strong tumor accumulation maintained to 24 hours with renal clearance and essentially complete elimination by 96 hours, raising tumor temperature to 55.5 degrees Celsius under irradiation compared to 34.9 degrees in controls.

The multimodal synergy these platforms enable is where the real therapeutic promise lies. Photothermal therapy increases cell membrane permeability and vascular perfusion, facilitating deeper penetration and enhanced uptake of co-delivered chemotherapeutics such as doxorubicin. Chitosan-based systems have been engineered to combine photothermal ablation with chemodynamic therapy, where acidic tumor conditions trigger the release of metal ions that catalyze the Fenton reaction, converting hydrogen peroxide into destructive hydroxyl radicals. Other chitosan platforms incorporate glucose oxidase to starve tumors of their energy supply, or nanozyme hybrids that induce ferroptosis, an iron-dependent form of regulated cell death particularly effective against multidrug-resistant cancer cells. Magnetic hyperthermia, where chitosan matrices embed superparamagnetic iron oxide nanoparticles guided by alternating magnetic fields, offers an alternative for deep-seated tumors where near-infrared light cannot reach.

Yet the review is refreshingly honest about the obstacles that stand between laboratory success and clinical reality. Despite remarkable preclinical efficacy, clinical translation of chitosan and hyaluronic acid-based nanophotothermal systems remains limited. The most advanced clinical experience with nanoparticle-mediated photothermal therapy comes from inorganic gold nanoshell platforms such as AuroLase, which demonstrated a favorable safety profile with no serious treatment-related adverse events and negative targeted biopsies in 68 percent of treated lesions one year after treatment. But bio-based systems face their own hurdles: batch-to-batch variability in polymer molecular weight and degree of deacetylation, unclear pharmacokinetics, the challenge of scaling laboratory fabrication techniques such as electrospinning and three-dimensional bioprinting to industrial production, and the heavy regulatory burden that multifunctional combination products must navigate.

The biological complexity of the tumor microenvironment presents perhaps the most fundamental challenge. The enhanced permeability and retention effect, long considered the cornerstone of passive nanoparticle tumor accumulation, varies considerably among patients and tumor types. CD44, the primary receptor targeted by hyaluronic acid, exists in multiple isoforms with differential expression across cancer subtypes and disease stages, meaning that receptor expression alone may be insufficient to predict targeting efficiency. The review argues that future clinical translation should focus on personalized strategies with quantitative evaluation of CD44 expression, selecting patients most likely to benefit from HA-mediated targeting rather than adopting a one-size-fits-all approach. Long-term biosafety also remains insufficiently characterized, with most preclinical studies assessing only acute cytotoxicity and short-term tumor suppression while neglecting chronic inflammation, immunogenicity, degradation products, and delayed organ accumulation.

What emerges from this comprehensive analysis is a vision of cancer therapy that is at once more precise and more humane than what conventional protocols can offer. By combining the engineering versatility of chitosan with the biological selectivity of hyaluronic acid, researchers are building nanoplatforms that can find tumors, deliver multiple therapeutic payloads on demand, generate lethal heat under external control, and report their own progress through imaging, all while degrading safely into components the body can process. The review’s structure-function perspective, comparing these two complementary biopolymers rather than simply cataloging materials, provides a framework that could accelerate the rational design of next-generation systems. As the author notes, the path from bench to bedside will require unprecedented collaboration among materials scientists, pharmaceutical technologists, oncologists, imaging specialists, toxicologists, manufacturers, and regulatory authorities. But if the trajectory of the past five years is any indication, the convergence of bio-based nanotechnology and photothermal medicine may be one of the most consequential developments in precision oncology this decade.

Subject of Research: Bio-based nanophotothermal drug delivery systems using chitosan and hyaluronic acid for multimodal synergistic cancer therapy

Article Title: Bio-based nanophotothermal systems as smart drug delivery platforms for multimodal synergistic cancer therapy—a review

Article References: Bio-based nanophotothermal systems as smart drug delivery platforms for multimodal synergistic cancer therapy—a review. (n.d.). https://doi.org/10.3389/fmedt.2026.1943029

Image Credits: AI Generated

DOI: 10.3389/fmedt.2026.1943029

Keywords: photothermal therapy, chitosan, hyaluronic acid, nanomedicine, drug delivery, cancer treatment, theranostics, stimuli-responsive nanoparticles, tumor targeting, CD44 receptor, multimodal therapy, biocompatible polymers