Smart nano-assembly from traditional Chinese medicine: Manganese-enhanced polysaccharide platform for orchestrated cancer chemo-immunotherapy.

The limitations of conventional cancer therapies have driven the development of precise, low-toxicity strategies. Natural products with bioactivity and self-assembly potential offer a basis for designing multifunctional nanomedicines combining chemotherapy, chemodynamic therapy (CDT), and immunotherapy. This study aimed to construct a novel pH-responsive nano-assembly by integrating immunomodulatory Polygonatum odoratum polysaccharide (POP), anticancer luteolin (LUT), and manganese ions (Mn2+) for CDT and immune activation. The design achieves synergistic multi-therapy while enhancing safety through stimuli-responsive release, avoidance of inactive carriers, and a simple preparation strategy. A pH-responsive crosslinker (FH) was designed to conjugate POP, LUT, and Mn2+ into LUT@POP-FH-Mn. The system was characterized for physicochemical properties, assembly mechanism, responsive release, and biosafety. Antitumor efficacy and synergistic mechanisms were evaluated in vitro and in vivo. Uniform nanoparticles (∼230 nm) were formed via boronate ester crosslinking, with Mn2+ and LUT loaded through hydrazone coordination and π‑π stacking. The system showed pH-responsive release under weak acidity and significantly enhanced efficacy over LUT alone, reducing IC50 to 0.22 μg/mL (A549) and 0.98 μg/mL (HeLa). The mechanism involved triple synergy: (1) LUT-induced oxidative stress and apoptosis; (2) Mn2+-mediated Fenton-like reactions generating hydroxyl radicals for lipid peroxidation; and (3) POP combined with Mn2+ activating dendritic cells and upregulating CD40, CD80, CD86, and MHC-II to initiate antitumor immunity. The LUT@POP-FH-Mn synergistically combines natural compounds and metal ions, improving drug delivery and efficacy through integrated chemotherapy, CDT, and immunotherapy. This work provides an innovative model for modernizing traditional Chinese medicine and demonstrates the promise of natural product-based nanomedicine for combined cancer therapy.