Abstract
Overcoming the hypoxic tumor microenvironment (TME) and immune suppression remains a significant challenge in solid bladder tumor therapies. This study introduces a translational system of nano-orchestrated magnetotactic-like system, integrating photosynthetic oxygenation, remote hyperthermia, and ferroptosis to achieve comprehensive tumor eradication and immune activation. The developed system, composed of electromagnetic-responsive iron oxide nanoparticles (IO NPs) encapsulated within a glycol chitosan (GCS) matrix and coated onto Chlorella (CHL; CHL-GCS-IO NPs), exhibited versatility for precise magnetic targeting, photothermal-hypertehrmia and photosynthesis-driven oxygen generation under light irradiation. The CHL enhanced oxygen production by continuously alleviating hypoxia, boosting both electromagnetic therapeutic efficacies and ferroptosis-induced tumor cell death. Moreover, the multimodal CHL-GCS-IO NPs reprogrammed the TME, facilitating immune activation by promoting macrophage polarization towards the proinflammatory M1 phenotype, engaging cytotoxic T cells and natural killer cells, programmed death ligand 1 (PD-L1) downregulation, and driving dendritic cell reprogramming towards improved antigen presentation. In vivo, this approachsuggested significant tumor growth inhibition and prevented recurrence in bladder cancer models, highlighting its potential for robust and durable anticancer immunity. This magnetotactic-like CHL platform presents a highly promising theranostic strategy, merging multimodal therapies with immune modulation to tackle both direct and systemic challenges of solid bladder tumors.