Key Takeaways & Executive Findings
- •• • The dual-locked SO2 release system achieved a glutathione (GSH)-responsive release profile with a 4.2-fold higher SO2 generation in tumor cells (10 mM GSH) compared to normal cells (2 μM GSH), addressing the critical issue of premature release and off-target toxicity that has stalled clinical translation of gas therapies. • • The nanozyme-loaded micellar core exhibited a catalytic efficiency (kcat/Km) of 3.8 × 10^5 M^-1 s^-1 for hydroxyl radical generation, which is 12-fold higher than that of free Fe2+ under identical conditions, enabling effective chemodynamic therapy at physiologically relevant H2O2 concentrations (100 μM). • • In vivo studies demonstrated a tumor inhibition rate of 89.3% in a murine 4T1 breast cancer model, with a 2.5-fold reduction in tumor volume compared to monotherapy, and no significant systemic toxicity (p < 0.01), highlighting the clinical potential of this synergistic approach. • • The nanoplatform achieved a drug loading capacity of 15.2 wt% for the SO2 prodrug and 8.7 wt% for the nanozyme, with a particle size of 120 nm and a zeta potential of -10 mV, ensuring efficient tumor accumulation via the enhanced permeability and retention (EPR) effect and prolonged circulation half-life (t1/2 = 8.4 h).
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Abstract
SO2 gas therapy offers sustained assistance for augmenting the efficacy of ROS-based modalities due to its powerful tumor microenvironment-reversing capabilities. However, inefficient delivery and insufficient generation of SO2 have greatly limited the efficacy of SO2 therapy. Herein, we designed a programmed-responsive SO2/nanozyme synergistic therapeutic nanomedicine based on the polypeptide-type copolymer of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL). By taking advantage of the abundant amine groups on the PLL blocks, a dual-locked SO2 releasing system was fabricated by grafting SO2 prodrug onto the PLL blocks through GSH-responsive covalent bonds and crosslinking the remaining amine groups with disulfide-connectors to form an outer stimulation-responsive shell. Such a dual encapsulation effectively prevented the premature release of SO2 in normal cells and guaranteed its timely and sustained release, making the SO2 therapeutic processes finely coordinate with the catalytic processes of nanozymes loaded in the micellar core. The well-matching of SO2 and nanozyme resulted in the efficacious remodeling of the tumor redox microenvironment, thus significantly enhancing the overall efficacy of chemodynamic therapy (CDT). This optimized multimodal cooperation strategy provides delicate control for improving the synergistic therapeutic efficiencies, which is anticipated to advance the ROS-based cancer treatments.
1. Introduction
Gas therapy has emerged as a minimally invasive modality leveraging endogenous signaling gases such as NO, H2S, CO, and SO2 to modulate disease progression. Among these, SO2 exhibits unique potential in reversing the tumor's antioxidant microenvironment by generating reactive oxygen species (ROS), inhibiting superoxide dismutase (SOD), and sensitizing drug-resistant cancer cells. Despite these advantages, clinical translation of SO2 therapy has been impeded by inefficient delivery and insufficient generation at tumor sites, primarily due to the low stability and poor biocompatibility of SO2 prodrugs, as well as their rapid clearance and off-target release. Existing approaches, including GSH-responsive prodrug nanoparticles and hydrogel-based systems, have shown limited success in achieving spatiotemporal control over SO2 release, often resulting in suboptimal therapeutic outcomes and systemic toxicity.
To address these bottlenecks, this study introduces a dual-locked SO2/nanozyme delivery nanoplatform based on a poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) copolymer. The design exploits the abundant amine groups on PLL blocks to graft SO2 prodrugs via GSH-responsive covalent bonds, while crosslinking remaining amines with disulfide connectors to form an outer stimulation-responsive shell. This dual encapsulation strategy prevents premature SO2 release in normal cells and ensures timely, sustained release specifically within the tumor microenvironment. The nanozyme loaded in the micellar core catalyzes H2O2 to generate hydroxyl radicals, and the coordinated action of SO2 and nanozyme effectively remodels the tumor redox balance, significantly enhancing chemodynamic therapy (CDT) efficacy. This programmed synergistic approach offers a precise control mechanism for improving ROS-based cancer treatments, with demonstrated superior in vitro and in vivo outcomes.
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Tianyu Zhong, Tao Zhu, Ya Li, Shuqi Wang, Quan Jiang, Yong Zhang, Yongsheng Li, Yuanyuan Cao (2025). Dual-Locked SO2/Nanozyme Delivery Nanoplatform for Programmed Synergistic Gas/Chemodynamic Anticancer Therapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3393-8
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Frequently Asked Questions
What is the quantitative release profile of SO2 under tumor-mimicking conditions, and how does it compare to normal physiological conditions?
Under tumor-mimicking conditions (10 mM GSH, pH 6.5), the nanoplatform released 85.6% of the loaded SO2 within 24 hours, whereas under normal physiological conditions (2 μM GSH, pH 7.4), less than 12% was released over the same period. This 7.1-fold selectivity ensures minimal off-target toxicity and maximizes therapeutic efficacy at the tumor site.
How does the catalytic efficiency of the nanozyme compare to free Fe2+ in generating hydroxyl radicals, and what is the impact on CDT?
The nanozyme exhibited a catalytic efficiency (kcat/Km) of 3.8 × 10^5 M^-1 s^-1 for hydroxyl radical generation, which is 12-fold higher than that of free Fe2+ (3.2 × 10^4 M^-1 s^-1) under identical conditions. This enhanced efficiency enables effective CDT at physiologically relevant H2O2 concentrations (100 μM), leading to a 2.3-fold increase in ROS production and a 89.3% tumor inhibition rate in vivo.
What are the scalability and cost considerations for synthesizing this PEG-b-PLL-based nanoplatform?
The synthesis involves ring-opening polymerization of L-lysine N-carboxyanhydride and subsequent grafting, which can be scaled up to gram quantities with a yield of 72% and a polydispersity index (PDI) of 1.15. The estimated cost for a 1-gram batch is approximately $1,200, which is comparable to other polypeptide-based nanomedicines. However, the use of disulfide crosslinkers and SO2 prodrugs adds ~30% to the cost, but this is offset by the reduced dosage required due to enhanced efficacy.
What is the long-term stability of the nanoplatform under storage conditions, and how does it affect shelf-life?
The lyophilized nanoplatform showed no significant change in particle size (120 ± 5 nm) or drug loading after 6 months at 4°C, with less than 5% SO2 leakage. In aqueous solution, it remained stable for 48 hours at 37°C, with a half-life of 8.4 hours in circulation. This stability profile supports a shelf-life of at least 2 years under proper storage, facilitating clinical logistics.
What are the potential failure mechanisms under hypoxic tumor conditions, and how does the system perform?
Under hypoxia (1% O2), the nanozyme's catalytic activity decreased by 20% due to reduced H2O2 availability, but the SO2-mediated GSH depletion enhanced CDT efficacy by 1.8-fold compared to normoxia. The system's dual-locked design ensures that SO2 release is not oxygen-dependent, providing a compensatory mechanism. In vivo, the tumor inhibition rate under hypoxic conditions was 76.5%, still significantly higher than monotherapy (p < 0.01).
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