M1-macrophage membrane-camouflaged nanoframeworks activate multiple immunity via calcium overload and...

Immunotherapy is a powerful weapon for inhibiting tumor metastasis, while its efficacy is significantly compromised in immunosuppressive tumor microenvironment (TME). To reverse TME, this work has developed biomimetic nanoframeworks with calcium overload and photo-sonosensitization capacity to activate multiple immunities for metastasis inhibition. The biomimetic nanoframeworks were prepared by the assembly of Ca²⁺ ions and Protoporphyrin IX (PpIX) into nanoframeworks (Ca-PpIX), and the encapsulation of M1 macrophage membrane (Ca-PpIX@M). They exhibit pH-dependent Ca²⁺ ions release, ¹O₂ generation and photothermal conversion under external near-infrared light and ultrasound stimuli. The Ca²⁺-overload and elevated ¹O₂ cause oxidative stress within cells, leading to efficient mitochondrial dysfunction. Successively, the mitochondrial dysfunction induces a reduction in adenosine triphosphate (ATP) levels to inhibit the HSP90 expression, improving photothermal ablation's efficacy. The photo-sonosensitization has the ability to repolarize macrophages with the ratio of M1/M2 macrophage increasing from 0.25 to 2.45, which is better than monoactivation. Importantly, the Ca-PpIX@M also can induce the process of immunogenic cell death, resulting in the maturation of dendritic cells (30.2 %) and activation of cytotoxic (12.4 %) and helper T cells (19.7 %), thereby enhancing antitumor immunity in vivo. As a result, tumor growth and metastasis have been significantly inhibited. This work offers insights into developing biomimetic nanoframeworks to reverse TME for activating multiple immunity.