Gradient-driven deep penetration of self-electrophoretic nanoparticles in acidic tumor microenvironments for enhanced antitumor therapy

Difficulty of nanomedicines to effectively penetrate the tumor core and achieve effective killing of tumor stem cells is an important factor leading to recurrence, metastasis and drug resistance of tumors. Strategies based on the tumor microenvironment offer new perspectives and approaches to address the challenges associated with deep tumor treatment. Here, we designed novel MgF₂@L-Arg nanoparticles (ML NPs) by integrating basic L-arginine into MgF₂. Under the endogenous acid gradient within the tumor, ML NPs selectively protonate their proximal amines, leading to spatial charge asymmetry. This promotes the sustained diffusion and permeation of ML NPs deep into the tumor, achieving a penetration distance of up to 197 μm. Moreover, aside from enabling synergistic effects in sonodynamic therapy (SDT) and gas therapy, ML NPs can reduce the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and heat shock protein 70 (HSP 70) within tumor cells, induce immunogenic cell death, and bind to the co-stimulatory molecule LFA-1 on the surface of tumor cells, thereby enhancing the specific cytotoxicity of CD8⁺ T cells. This mechanism significantly improves the immune response against cancer cells and effectively suppresses tumor metastasis. Our research proposes a viable new strategy for the deep penetration of nanoparticles into tumors and for effective deep tumor treatment, demonstrating the tremendous potential of such materials in enhancing anti-tumor efficacy.