On September 19, 2025, Xu et al. from the Key Laboratory of Marine Drugs of the Ministry of Education, and related institutions published an article in the journal Marine Drugs titled "Novel pH-Responsive PSS-Loaded Chitosan Matrix Nanoparticles Ameliorate Pressure Overload-Induced Cardiac Hypertrophy." This study focuses on addressing the therapeutic challenge of pressure overload-induced cardiac hypertrophy. It designed and validated a pH-responsive propylene glycol alginate sulfate sodium (PSS)-loaded Chitosan Matrix Nanoparticle (TMC-GA/HP55@PSS). Prepared via electrostatic self-assembly, this nanoparticle exhibits high encapsulation efficiency, gastric stability, sustained intestinal release, and favorable biosafety. Both in vitro and in vivo experiments confirmed that it ameliorates cardiac hypertrophy, with superior efficacy compared to free PSS, providing crucial data for the formulation innovation and clinical application of PSS.

Research Background

The therapeutic agent PSS, a marine sulfated polysaccharide drug, shows immense promise in treating cardiovascular diseases due to its anti-inflammatory and cardioprotective properties. However, as a large, water-soluble macromolecule, PSS suffers from extremely poor oral bioavailability. It is highly susceptible to degradation by the strong acids and enzymes in the gastrointestinal tract, and its size limits passive absorption across the intestinal barrier. The foundational research challenge was thus to design a robust, orally available Drug Delivery System (DDS). By leveraging the unique physicochemical properties of chitosan, a naturally abundant and biocompatible marine polymer, the authors were able to construct a nanostructure that simultaneously offers gastric protection, enhances mucoadhesion, and facilitates intestinal uptake, transforming PSS from an injectable-only drug candidate into a viable oral therapeutic.

Fig.1 The oral absorption process of PSS and TMC-GA/HP55@PSS. (Xu, et al., 2025)

Research Results

• Engineering a pH-Responsive Marine Glycan Matrix

The foundation of this study is the creation of a sophisticated nanocarrier system designed to overcome the hostile gastrointestinal environment. The authors ingeniously fabricated core chitosan Matrix nanoparticles using N,N,N-trimethyl chitosan (TMC) and glycocholic acid (GA)—both derived from or utilizing Marine and Natural Biomolecules. This initial core, designated TMC-GA@PSS, provided a basic matrix for PSS encapsulation. The critical innovation was the subsequent surface modification with hydroxypropyl methylcellulose phthalate (HP55). This addition resulted in the final nanocarrier, TMC-GA/HP55@PSS, which exhibits superior pH-responsive characteristics, ensuring minimal drug release at the highly acidic pH of the stomach (pH 1.2) and maximum therapeutic payload release in the mildly alkaline environment of the intestine (pH 6.8).

Fig.2 Preparation of PSS nanoparticles. (Xu, et al., 2025)

• Optimized Intestinal Drug Release and Biosafety

A detailed in vitro release study confirmed the optimal functionality of the HP55-modified nanoparticles. The TMC-GA/HP55@PSS system demonstrated superior drug retention in simulated gastric fluid, successfully protecting the PSS payload. In contrast, it showed a rapid and sustained release profile in simulated intestinal fluid, achieving nearly 70% PSS release within 72 hours. This tailored release profile is crucial for maximizing therapeutic efficacy by ensuring the active agent is available at the site of absorption. Furthermore, comprehensive Biosafety Evaluations, including the CCK-8 assay on H9C2 cardiomyocytes and hemolytic tests on rat red blood cells, confirmed the excellent cytocompatibility and minimal hemolytic activity of the nanoparticles, validating their potential for clinical translation.

Fig.3 In vitro safety evaluation of PSS and its nanoparticles. (Xu, et al., 2025)

• Ameliorating Pressure Overload-Induced Cardiac Hypertrophy

The ultimate measure of the nanocarrier's success was its in vivo therapeutic performance in a rat model of pressure overload-induced cardiac hypertrophy, achieved via transverse aortic constriction (TAC). Oral administration of the optimized TMC-GA/HP55@PSS nanoparticles, loaded with PSS, demonstrated a significant protective effect. Treatment successfully attenuated the hypertrophy of cardiomyocytes, reduced the expression of molecular markers associated with heart failure, and notably inhibited myocardial fibrosis. These physiological and molecular findings confirm that the smart, orally delivered marine glycodrug system effectively reached its target, delivered its payload, and mitigated the pathological progression of cardiac hypertrophy, an important risk factor for heart failure.

Conclusion

This study is a landmark achievement in marine glycobiology and nanomedicine, successfully developing a novel oral delivery platform that utilizes two pivotal Marine-derived Biopolymers: Chitosan as the structural backbone and PSS as the active therapeutic glycan. The engineered pH-responsive TMC-GA/HP55@PSS nanoparticles not only solved the critical bioavailability problem for PSS but also demonstrated significant efficacy in a challenging model of cardiac disease. This innovative application underscores the immense, untapped potential of marine glycans as both advanced pharmaceutical excipients and potent therapeutic agents. The findings pave a clear path toward the development of stable, non-invasive, and highly effective oral glycodrug therapies for chronic conditions like heart failure.