Igniting Tumor Microenvironment in Triple-Negative Breast Cancer using a Mannose/Hyaluronic Acid Dual-Coated Ganoderma Polysaccharide-Superparamagnetic Iron Oxide Nanocomplex for Combinational Therapies

Eliciting tumour microenvironment (TME) activation in triple-negative breast cancer (TNBC) is crucial for effective anti-tumour therapies. The aim of this study is to employ pharmaceutical approaches to precisely deliver Ganoderma polysaccharide (GPS) to tumour sites, thereby enhancing TME activation. We first established a direct link between the accumulation of GPS within tumours and its efficacy in the TME activation. Building upon this insight, we then engineered a mannose/hyaluronic acid dual-coated GPS-loaded superparamagnetic iron oxide nanocomplex (Man/HA/GPS-SPIONs) with a particle size of 33.8 ± 1.6 nm and a zeta potential of -22.4 ± 3.5 mV, capable of precise tumour accumulation through magnet-assisted targeting and internalisation by tumour-associated macrophages (TAMs) and tumour cells, facilitated by dual ligand modification. In vitro, Man/HA/GPS-SPIONs effectively induced M1 polarisation of macrophages (CD86+ cells: 38.6 ± 2.8%), curbed 4T1 cell proliferation (viability: 47.3 ± 2.9%) and heightened Th1 cytokine release. Significantly, in vivo, Man/HA/GPS-SPIONs notably suppressed tumour growth (tumour index: 0.048 ± 0.005), fostered M1 polarisation of TAMs (CD45+F4/80+CD86+ cells: 26.1 ± 7.2%), consequently bolstering intratumoural T cytotoxic cells. This enhancement was intricately tied to the efficient co-delivery of GPS and iron ions to the tumours, made possible by the Man/HA/GPS-SPIONs delivery system. The synergistic effects with paclitaxel (PTX, inhibition rate: 61.2 ± 4.3%) and PD-1 inhibitors (inhibition rate: 69.8 ± 7.6%) underscored the translational potential of this approach. By harnessing a well-conceived iron-based drug delivery strategy, this study amplifies the tumour immune modulatory potential of natural polysaccharides, offering insightful guidance for interventions in the TME and synergistic therapies.