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Nanomechanical action opens endo-lysosomal compartments.

ABSTRACT: Endo-lysosomal escape is a highly inefficient process, which is a bottleneck for intracellular delivery of biologics, including proteins and nucleic acids. Herein, we demonstrate the design of a lipid-based nanoscale molecular machine, which achieves efficient cytosolic transport of biologics by destabilizing endo-lysosomal compartments through nanomechanical action upon light irradiation. We fabricate lipid-based nanoscale molecular machines, which are designed to perform mechanical movement by consuming photons, by co-assembling azobenzene lipidoids with helper lipids. We show that lipid-based nanoscale molecular machines adhere onto the endo-lysosomal membrane after entering cells. We demonstrate that continuous rotation-inversion movement of Azo lipidoids triggered by ultraviolet/visible irradiation results in the destabilization of the membranes, thereby transporting cargoes, such as mRNAs and Cre proteins, to the cytoplasm. We find that the efficiency of cytosolic transport is improved about 2.1-fold, compared to conventional intracellular delivery systems. Finally, we show that lipid-based nanoscale molecular machines are competent for cytosolic transport of tumour antigens into dendritic cells, which induce robust antitumour activity in a melanoma mouse model.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC10589329 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Nanomechanical action opens endo-lysosomal compartments.

Zhao Yu Y Ye Zhongfeng Z Song Donghui D Wich Douglas D Gao Shuliang S Khirallah Jennifer J Xu Qiaobing Q

Nature communications 20231020 1

Endo-lysosomal escape is a highly inefficient process, which is a bottleneck for intracellular delivery of biologics, including proteins and nucleic acids. Herein, we demonstrate the design of a lipid-based nanoscale molecular machine, which achieves efficient cytosolic transport of biologics by destabilizing endo-lysosomal compartments through nanomechanical action upon light irradiation. We fabricate lipid-based nanoscale molecular machines, which are designed to perform mechanical movement by ...[more]

PMID: 37863882

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Project description:Recessive loss-of-function mutations in ATP13A2 (PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson's disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death. Moreover, ATP13A2 knockdown induced an ATF4-CHOP-dependent stress response following rotenone exposure. MitoROS and ATF4-CHOP were blocked by MitoTEMPO, a mitochondrial antioxidant, suggesting that the impact of ATP13A2 on MitoROS may relate to the antioxidant properties of spermine. Pharmacological inhibition of intracellular polyamine synthesis with α-difluoromethylornithine (DFMO) also increased MitoROS and ATF4 when ATP13A2 was deficient. The polyamine transport activity of ATP13A2 was required for lowering rotenone/DFMO-induced MitoROS, whereas exogenous spermine quenched rotenone-induced MitoROS via ATP13A2. Interestingly, fluorescently labeled spermine uptake in the mitochondria dropped as a consequence of ATP13A2 transport deficiency. Our cellular observations were recapitulated in vivo, in a Caenorhabditis elegans strain deficient in the ATP13A2 ortholog catp-6 These animals exhibited a basal elevated MitoROS level, mitochondrial dysfunction, and enhanced stress response regulated by atfs-1, the C. elegans ortholog of ATF4, causing hypersensitivity to rotenone, which was reversible with MitoTEMPO. Together, our study reveals a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export.

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Nanomechanical action opens endo-lysosomal compartments.

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Nanomechanical action opens endo-lysosomal compartments.

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