The battle against cancer has been going on for a century. On the other hand, this devastating disease remains one of the leading causes of death worldwide. According to the GLOBOCAN 2020 report by the International Agency for Research on Cancer, nearly 10 million people lost their lives to cancer globally in 2020. [1]. Though the fight against cancer is far from being ended, the knowledge we now have about its biology, diagnosis, and prognosis has been invaluable. Traditional remedies used for hundreds of years have recently received a lot of attention for preventing and curing cancer.

Honokiol (HK) is a critical bioactive biphenolic compound isolated from Magnolia officinalis, Magnolia obovata, and Magnolia grandiflora bark and leaf extracts [2]. It has been extensively applied in traditional Chinese medicine for managing gastrointestinal disorders, stroke, anxiety, cough, and allergic conditions, and it also exhibits antithrombotic, antidepressant, antiemetic, and antibacterial properties. [3], [4], [5], [6], [7] In vitro and in vivo research have demonstrated the effectiveness of HK in treating [3] a variety of malignancies [8], [9], including skin cancer, and hepatocellular carcinoma [10], breast cancer [11], lung cancer [12], colon cancer [13], prostate cancer [14]. Its heat of evaporation is 67.7 kJ/mol, indicating poor water solubility, which is a major impediment for HK's clinical applications [15]. Currently, liposome-encapsulated HK is undergoing clinical trials (CTR20170822) in China for patients with advanced non-small cell lung cancer, glioblastoma, and meningioma [16], [17], These developments underscore the need to further investigate and refine drug delivery systems to enhance its therapeutic efficacy [18].

Several attempts have been made to develop nanotechnology-based carrier-mediated delivery systems for HK, including nanomicellar [19], nanoparticles [20], nanosuspensions [21], liposomes [22], and polymeric micelle [23], [24]. These delivery systems have benefits over conventional drug delivery and could make lipophilic drugs easier to dissolve in water, regulate their release, and boost their bioavailability [25], [26]. In addition, nanocapsule-based drug delivery systems provide biodegradability, high drug loading, efficient cellular uptake, favorable intratumorally biodistribution, and potential for cancer targeting functionalization [27], [28]. High drug loading ratio and strong responsiveness to single or multiple stimuli are features of some well-designed nanocarriers, enabling precise control of drug release at tumor sites [29], [30].

While prolonged blood circulation of nanocarriers enhances therapeutic efficacy, it may also increase drug leakage, reducing effectiveness, especially for cargos loaded via weak interactions such as π-stacking, Van der Waals forces, and hydrogen bonding [31], [32]. The tumor microenvironment possesses characteristics that differ from normal tissues in that it has a high glutathione (GSH) level, low pH, and hypoxia [33], [34]. A current research hotspot is the incorporation of tumor microenvironment-sensitive monomers into material systems to enhance drug efficacy [35]. Due to the intracellular GSH concentration in tumor cells is approximately 500–1000 fold higher than that in the extracellular fluid and exceeds that in normal cells by more than 4-fold, disulfide linker-containing monomers are widely utilized as GSH-responsive units in biomedical research [36]. Xiang et al. developed a self-assembled nanoparticle platform composed of amphiphilic lipid-polyethylene glycol (PEG) conjugates for the efficient delivery of a Pt(IV) prodrug. This system resists thiol-mediated detoxification through glutathione (GSH) depletion, offering a promising strategy to synergistically enhance both the safety and efficacy of platinum-based chemotherapy [37]. Halder and colleagues designed a hydrogel based on ultrasmall peptides that specifically responds to elevated levels of GSH in the tumor microenvironment, enabling controlled drug release. This platform achieved sustained and targeted delivery of doxorubicin in a murine breast cancer model, resulting in notable therapeutic outcomes [38].

Cross-linked polyphosphazene nanomaterials could be synthesized by reacting the core monomer hexachlorocyclotriphosphazene (HCCP) with functionally active molecules such as phenols or amino acids, creating versatile systems for biological applications [39], [40], [41], [42], [43], [44]. Polyphosphazenes [45]offer great biocompatibility and biodegradability and could be degraded into innoxious biological components like ammoniums and phosphates in vivo [46], enabling polyphosphazenes with the potential for biological applications.

Herein we disclose the design and preparation of HCCP-CysM-HK as a biodegradable GSH responsive nano-drug for enhanced therapeutic effect. Both in vitro and in vivo evaluations indicate that this nano-formulation is highly efficacious and biocompatible, possessing the potential for further development as a cancer therapy.Scheme 1