Medicinal Plant Research 2024, Vol.14, No.6, 358-370 http://hortherbpublisher.com/index.php/mpr 361 Nanotechnology-based modification methods are also emerging, including the construction of selenium nanoparticles or black phosphorus nanosheets and the loading of cordyceps polysaccharides on them. These methods provide new strategies for targeted drug delivery and synergistic anticancer therapy (Zhang et al., 2023; Wang et al., 2024). Such nanocarriers can not only improve cellular uptake efficiency and bioavailability, but also achieve the synergistic delivery of multiple therapeutic factors. For example, selenium nanoparticle complexes exhibited potent antitumor activity by activating intrinsic and extrinsic apoptosis pathways, while black phosphorus-cordyceps polysaccharide nanocomposites showed significant synergistic effects in photothermal therapy and immunotherapy models. 4 Structure-Activity Relationship of Modified Cordyceps Polysaccharides 4.1 Effects of modification degree and substitution pattern The effects of Cordyceps polysaccharides vary greatly depending on how they are modified. Sulfonation is one of the commonly used methods. Studies have found that when the degree of sulfonation (DS) is between 1.2-1.5, the anti-tumor activity is the strongest. Exceeding this range may backfire and affect structural stability (Jing et al., 2015). Selenization is similar. Adding an appropriate amount can indeed enhance the ability to induce apoptosis, but too much selenium may destroy the original structure of the polysaccharide (Liu et al., 2017; Sun et al., 2018; Zhang et al., 2023). Acetylation is characterized by "too much is as bad as too little". Only when it is controlled within the appropriate range can it play a positive role (Qi et al., 2020; Zhao et al., 2023). In addition to “how much to add”, “where” to add is also critical. For example, substitution at the C-6 position is more likely to affect the three-dimensional configuration of the polysaccharide, improve its ability to bind to the receptor, and thus enhance the immunomodulatory effect (Qiao et al., 2019; Li et al., 2025). Some polysaccharides with structural advantages, such as highly branched, low-molecular-weight galactoglucomannan, not only have strong immune activity, but are also particularly suitable for use as drug delivery carriers (Jing et al., 2014; Bi et al., 2018). Choosing the right structure and combining it with moderate modification will make the activity performance more stable. 4.2 Role of molecular weight and conformational features Molecular weight is an important factor that affects the bioavailability and function of Cordyceps polysaccharides. Low molecular weight polysaccharides (like 2-20 kDa) are usually easier for cells to take in. They also dissolve better in water and show stronger immune-regulating effects. Because of this, they are often used as drug carriers or adjuvants (Jing et al., 2014; Shi et al., 2020; Dai et al., 2024a; b; Li et al., 2025). On the other hand, high molecular weight polysaccharides (over 100 kDa) may have stronger immune-boosting and direct anti-tumor effects. But their bioavailability in the body is lower, and they don’t move through tissues as easily (Tan et al., 2023; He et al., 2019; Zhu et al., 2024). By adjusting extraction and processing methods—like changing the temperature, using ultrasound, or adding enzymes—we can control the molecular weight and improve the anti-tumor effects of Cordyceps polysaccharides (Zhu et al., 2014; 2016; Nurmamat et al., 2018). For example, Nurmamat et al. (2018) looked into how extracting at different temperatures (4 °C and 80 °C) changes the chemical structure and anti-tumor activity of Cordyceps polysaccharides. They found that the polysaccharide called CMPs-4, which was extracted at low temperature (4 °C), had a molecular weight around 188 kDa, was rich in glucose, and had a more stable triple-helix structure. In contrast, CMPs-80, extracted at high temperature (80 °C), had a higher molecular weight (about 308 kDa) and was richer in rhamnose and galactose. Lab tests showed that CMPs-4 was much better at causing human esophageal cancer Eca-109 cells to undergo apoptosis. It also had a stronger concentration-dependent effect when compared with CMPs-80 (Figure 1). Structural features like the triple-helix shape and highly branched chains are closely linked to stronger biological activity. The triple-helix structure helps the polysaccharide resist enzyme breakdown and makes it more stable. At the same time, highly branched or porous chain structures can create more surface area to interact with immune receptors, which helps activate immune cells (Jing et al., 2014; Bi et al., 2018; Li et al., 2025). For instance, a low
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