Fusogenic Cell-Derived nanocarriers for cytosolic delivery of cargo inside living cells.

A surface-engineered cell-derived nanocarrier was developed for efficient cytosolic delivery of encapsulated biologically active molecules inside living cells. Thus, a combination of aromatic-labeled and cationic lipids, instrumental in providing fusogenic properties, was intercalated into the biomimetic shell of self-assembled nanocarriers formed from cell membrane extracts. The nanocarriers were loaded, as a proof of concept, with either bisbenzimide molecules, a fluorescently labeled dextran polymer, the bicyclic heptapeptide phalloidin, fluorescently labeled polystyrene nanoparticles or a ribonucleoprotein complex (Cas9/sgRNA). The demonstrated nanocarriers fusogenic behavior relies on the fusogen-like properties imparted by the intercalated exogenous lipids, which allows for circumventing lysosomal storage, thereby leading to efficient delivery into the cytosolic milieu where cargo regains function.

Biomimetic cell-derived nanocarriers in cancer research.

Nanoparticles have now long demonstrated capabilities that make them attractive to use in biology and medicine. Some of them, such as lipid nanoparticles (SARS-CoV-2 vaccines) or metallic nanoparticles (contrast agents) are already approved for their use in the clinic. However, considering the constantly growing body of different formulations and the huge research around nanomaterials the number of candidates reaching clinical trials or being commercialized is minimal. The reasons behind being related to the "synthetic" and "foreign" character of their surface. Typically, nanomaterials aiming to develop a function or deliver a cargo locally, fail by showing strong off-target accumulation and generation of adverse responses, which is connected to their strong recognition by immune phagocytes primarily. Therefore, rendering in negligible numbers of nanoparticles developing their intended function. While a wide range of coatings has been applied to avoid certain interactions with the surrounding milieu, the issues remained. Taking advantage of the natural cell membranes, in an approach that resembles a cell transfer, the use of cell-derived surfaces has risen as an alternative to artificial coatings or encapsulation methods. Biomimetic technologies are based on the use of isolated natural components to provide autologous properties to the nanoparticle or cargo being encapsulated, thus, improving their therapeutic behavior. The main goal is to replicate the (bio)-physical properties and functionalities of the source cell and tissue, not only providing a stealthy character to the core but also taking advantage of homotypic properties, that could prove relevant for targeted strategies. Such biomimetic formulations have the potential to overcome the main issues of approaches to provide specific features and identities synthetically. In this review, we provide insight into the challenges of nano-biointerfaces for drug delivery; and the main applications of biomimetic materials derived from specific cell types, focusing on the unique strengths of the fabrication of novel nanotherapeutics in cancer therapy.

Author Correction: Identification and characterization of Cardiac Glycosides as senolytic compounds.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Plasmonic Cell-Derived Nanocomposites for Light-Controlled Cargo Release inside Living Cells.

Translating the potential of thermoplasmonics to cell-derived nanomaterials offers exciting opportunities to fabricate beyond state-of-art artificial biomimetic nanocomposites that upon illumination perform active tasks such as delivery of cargo in complex, dynamic media such as the cytosol of cells. Cell-derived nanoparticles have shown stunning potential to implement cell-specific functions, such as long blood circulation or targeting capabilities, into advanced drug delivery nanosystems. The biomimicry nanotechnology has now advanced to offer new and exciting opportunities to improve the commonly poor in vivo performance of most current nanomedicines, including evading the immune system and targeting specific tissues such as tumors, the latest remaining among the most wanted breakthroughs in nanomedicine. However, the use of cell-derived nanocomposites as stimulus-controlled drug delivery agents remains virtually unexplored. This study reports the fabrication of a plasmonic cell-derived nanocomposite by integrating near-infrared active gold nanorods in its structure. As a proof of concept, the plasmonic nanomembranes are loaded with cell non-permeant antibodies, which upon near-infrared stimulation can be released from the plasmonic nanomembranes into the cytosol of living cells, without impairing cell viability or the antibodies' function. These results set the stage for the development of photoactive cell-derived nanocarriers, which in addition to cell-specific functions promise straightforward access to spatiotemporal-controlled intracellular delivery of antibodies.

Identification and characterization of Cardiac Glycosides as senolytic compounds.

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.