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A size-shrinkable matrix metallopeptidase-2-sensitive delivery nanosystem improves the penetration of human programmed death-ligand 1 siRNA into lung-tumor spheroids.

ABSTRACT: Given the maturation of small-interfering RNA (siRNA) techniques with nanotechnology, and because overexpression of human programmed death-ligand 1 (PD-L1) is crucial for T cell inactivation and immunosuppression of the tumor microenvironment, application of siRNA-PD-L1 has demonstrated positive progress in preclinical studies; however, the limited penetration of this compound into solid tumors remains a challenge. To decrease PD-L1 expression and increase the penetration efficacy of solid tumors, we synthesized a novel tumor-microenvironment-sensitive delivery polymer by conjugating hyaluronic acid (HA) to polyethyleneimine (PEI), with a matrix metalloproteinase-2 (MMP-2)-sensitive peptide acting as the linker (HA-P-PEI), for use in delivery of PD-L1-siRNA. Concurrent synthesis of a linker-less HA-PEI compound allowed confirmation that negatively charged siRNA can be complexed onto the positively charged HA-PEI and HA-P-PEI compounds to form nanoparticles with the same particle size and uniform distribution with serum stability. We found that the size of the HA-P-PEI/siRNA nanoparticles decreased to <10 nm upon addition of MMP-2, and that H1975 cells overexpressing CD44, PD-L1, and MMP-2 aided confirmation of the delivery efficacy of the HA-P-PEI/siRNA nanocomplexes. Additionally, the use of HA-P-PEI caused less cytotoxicity than PEI alone, demonstrating its high cellular uptake. Moreover, pretreatment with MMP-2 increased nanocomplex tumor permeability, and western blot showed that HA-P-PEI/PD-L1-siRNA efficiently downregulated the PD-L1 expression in H1975 cells. These results demonstrated a novel approach for siRNA delivery and tumor penetration for future clinical applications in cancer treatment.

SUBMITTER: Wen J

PROVIDER: S-EPMC8183518 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFollowing an acute insult, macrophages regulate renal fibrogenesis through the release of various factors that either encourage the synthesis of extracellular matrix synthesis or the degradation of matrix via endocytosis, proteolysis, or both. However, the roles of infiltrating versus resident myeloid cells in these opposing processes require elucidation. The transcription factor Twist1 controls diverse essential cellular functions through induction of several downstream targets, including matrix metalloproteinases (MMPs). In macrophages, Twist1 can influence patterns of cytokine generation, but the role of macrophage Twist1 in renal fibrogenesis remains undefined.MethodsTo study Twist1 functions in different macrophage subsets during kidney scar formation, we used two conditional mutant mouse models in which Twist1 was selectively ablated either in infiltrating, inflammatory macrophages or in resident tissue macrophages. We assessed fibrosis-related parameters, matrix metallopeptidase 13 (MMP13, or collagen 3, which catalyzes collagen degradation), inflammatory cytokines, and other factors in these Twist1-deficient mice compared with wild-type controls after subjecting the animals to unilateral ureteral obstruction. We also treated wild-type and Twist1-deficient mice with an MMP13 inhibitor after unilateral ureteral obstruction.ResultsTwist1 in infiltrating inflammatory macrophages but not in resident macrophages limited kidney fibrosis after ureteral obstruction by driving extracellular matrix degradation. Moreover, deletion of Twist1 in infiltrating macrophages attenuated the expression of MMP13 in CD11b+Ly6Clo myeloid cells. Inhibition of MMP13 abrogated the protection from renal fibrosis afforded by macrophage Twist1.ConclusionsTwist1 in infiltrating myeloid cells mitigates interstitial matrix accumulation in the injured kidney by promoting MMP13 production, which drives extracellular matrix degradation. These data highlight the complex cell-specific actions of Twist1 in the pathogenesis of kidney fibrosis.

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A size-shrinkable matrix metallopeptidase-2-sensitive delivery nanosystem improves the penetration of human programmed death-ligand 1 siRNA into lung-tumor spheroids.

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