Genetically Engineering Cell Membrane‐Coated BTO Nanoparticles for MMP2‐Activated Piezocatalysis‐Immunotherapy

Abstract

Tumor immunotherapy based on immune checkpoint blockade (ICB) still suffers from low host response rate and non‐specific distribution of immune checkpoint inhibitors, greatly compromising the therapeutic efficiency. Herein, cellular membrane stably expressing matrix metallopeptidase 2 (MMP2)‐activated PD‐L1 blockades is engineered to coat ultrasmall barium titanate (BTO) nanoparticle for overcoming the immunosuppressive microenvironment of tumors. The resulting M@BTO NPs can significantly promote the BTO's tumor accumulation, while the masking domains on membrane PD‐L1 antibodies are cleaved when exposure to MMP2 highly expressed in tumor. With ultrasound (US) irradiation, M@BTO NPs can simultaneously generate reactive oxygen species (ROS) and O2 based on BTO mediated piezocatalysis and water splitting, significantly promoting the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and improving the PD‐L1 blockade therapy to the tumor, resulting in effective tumor growth inhibition and lung metastasis suppression in a melanoma mouse model. This nanoplatform combines MMP2‐activated genetic editing cell membrane with US responsive BTO for both immune stimulation and specific PD‐L1 inhibition, providing a safe and robust strategy in enhancing immune response against tumor.

A metal–organic framework-integrated composite for piezocatalysis-assisted tumour therapy: design, related mechanisms, and recent advances

“…7a). 70 In the piezoelectric degradation experiments, RhB in the M@BTO + US group was completely degraded after 100 min of US irradiation, indicating its excellent piezocatalytic ROS generation capacity. The oxygen generation of M@BTO in deoxygenated deionized water showed that M@BTO can piezocatalytically split water to produce oxygen, which can regulate the hypoxia of the TME.…”

“…69 Among these treatments, dynamic therapy can produce ROS to kill tumour cells, induce immunogenic cell death (ICD), release tumour-associated antigens (TAAs), and enhance tumour-specific immune responses. 70 However, dynamic…”

“…69 Among these treatments, dynamic therapy can produce ROS to kill tumour cells, induce immunogenic cell death (ICD), release tumour-associated antigens (TAAs), and enhance tumour-specific immune responses. 70 However, dynamic therapy requires the consumption of a large amount of oxygen, which can aggravate the hypoxia of tumour tissue and affect the immune response of T cells. 71 Given the properties of piezocatalysts that can catalyse water molecules to produce oxygen and ROS under US irradiation, the strategy of combining piezocatalysis and immunotherapy shows great potential.…”

Genetically Engineered‐Cell‐Membrane Nanovesicles for Cancer Immunotherapy

“…Thus, Liang et al recently constructed M-𝛼PD-L1 NVs expressing a matrix metallopeptidase-2 (MMP-2)-activating lock masking on 𝛼PD-L1 (M-𝛼PD-L1) through ge-netic engineering, which can avoid 𝛼PD-L1 binding with normal tissues. [114] Furthermore, high MMP-2 expression in tumors cleaves the curling peptides of the MMP-2-activating lock, exposing 𝛼PD-L1 and blocking the PD-1-PD-L1 signaling axis at the cancer site, providing a promising strategy to enhance cancer immunotherapy. Similarly, Wang and co-workers obtained CMNs overexpressing PD-L1 through genetic engineering and coated them on PLGA NPs to prepare mesenchymal stem cell (MSC)-PD-L1 + NPs used to reduce immune-related adverse events induced by ICIs.…”

Genetically Engineered Cell Membrane-Coated Nanoparticles with High-Density Customized Membrane Receptor for High-Performance Drug Lead Discovery

“…In recent years, cell membrane-coated nanoparticles have been extensively investigated for biomedical applications, such as drug delivery, , immunotherapy, − biological neutralization , and phototherapy. − By combining synthetic nanoparticle cores with naturally derived cell membrane layers, they inherit the highly complex functionalities of the source cells . These biomimetic nanoparticles possess numerous favorable advantages, including high biocompatibility, reduced toxicity, and specific targeting ability .…”