Organelle remodeling enhances mitochondrial ATP disruption for blocking neuro-pain signaling in bone tumor therapy

Cancer neuroscience has revealed the pivotal role of neural pathways in tumor progression and cancer-associated pain, particularly in bone metastases. To address both tumor growth and pain, we developed a novel nanomedicine strategy that targets mitochondrial dysfunction in cancer cells. The engineered H-MnCa/3MA-ALD nanoparticle system combines hollow mesoporous manganese-calcium (H-MnCa) nanoparticles functionalized with alendronate (ALD) for bone targeting, and loaded with 3-Methyladenine (3MA) to inhibit autophagy. This system disrupts mitochondrial ATP production, exploiting the inherent vulnerability of mitochondria to oxidative stress, and enhances reactive oxygen species (ROS) generation. The elevated ROS selectively induces cancer cell death while also reducing the secretion of nerve growth factor (NGF). This dual-action mechanism not only inhibits tumor growth and metastasis but also alleviates cancer-induced bone pain by downregulating neuro-pain mediators such as p-STAT-3 and NGF. This approach overcomes traditional chemodynamic therapy (CDT) limitations, ensuring targeted mitochondrial damage and apoptosis while preventing protective mitophagy. In vivo studies further confirm that H-MnCa/3MA-ALD provides effective tumor eradication and pain relief, offering a comprehensive solution for both cancer progression and pain management.