Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy.

BACKGROUND: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. METHODS: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. RESULTS: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. CONCLUSIONS: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

Towards a More Efficient Breast Cancer Therapy Using Active Human Cell Membrane-Coated Metal-Organic Frameworks.

The recent description of well-defined molecular subtypes of breast cancer has led to the clinical development of a number of successful molecular targets. Particularly, triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with historically poor outcomes, mainly due to the lack of effective targeted therapies. Recent progresses in materials science have demonstrated the impressive properties of metal-organic framework nanoparticles (NPs) as antitumoral drug delivery systems. Here, in a way to achieve efficient bio-interfaces with cancer cells and improve their internalization, benchmarked MIL-100(Fe) NPs were coated with cell membranes (CMs) derived from the human TNBC cell line MDA-MB-468. The prepared CMs-coated metal-organic framework (CMs_MIL-100(Fe)) showed enhanced colloidal stability, cellular uptake, and cytotoxicity in MDA-MB-468 cells compared to non-coated NPs, paving the way for these human CMs-coated MIL-100(Fe) NPs as effective targeted therapies against the challenging TNBC.

Exploring the Impact of Nanoparticle Stealth Coatings in Cancer Models: From PEGylation to Cell Membrane-Coating Nanotechnology.

Nanotechnological platforms offer advantages over conventional therapeutic and diagnostic modalities. However, the efficient biointerfacing of nanomaterials for biomedical applications remains challenging. In recent years, nanoparticles (NPs) with different coatings have been developed to reduce nonspecific interactions, prolong circulation time, and improve therapeutic outcomes. This study aims to compare various NP coatings to enhance surface engineering for more effective nanomedicines. We prepared and characterized polystyrene NPs with different coatings of poly(ethylene glycol), bovine serum albumin, chitosan, and cell membranes from a human breast cancer cell line. The coating was found to affect the colloidal stability, adhesion, and elastic modulus of NPs. Protein corona formation and cellular uptake of NPs were also investigated, and a 3D tumor model was employed to provide a more realistic representation of the tumor microenvironment. The prepared NPs were found to reduce protein adsorption, and cell-membrane-coated NPs showed significantly higher cellular uptake. The secretion of proinflammatory cytokines in human monocytes after incubation with the prepared NPs was evaluated. Overall, the study demonstrates the importance of coatings in affecting the behavior and interaction of nanosystems with biological entities. The findings provide insight into bionano interactions and are important for the effective implementation of stealth surface engineering designs.

Effect of the Protein Corona Formation on Antibody Functionalized Liquid Lipid Nanocarriers.

The main aim of this study is to report basic knowledge on how a protein corona (PC) could affect or modify the way in which multifunctionalized nanoparticles interact with cells. With this purpose, we have firstly optimized the development of a target-specific nanocarrier by coupling a specific fluorescent antibody on the surface of functionalized lipid liquid nanocapsules (LLNCs). Thus, an anti-HER2-FITC antibody (αHER2) has been used, HER2 being a surface receptor that is overexpressed in several tumor cells. Subsequently, the in vitro formation of a PC has been developed using fetal bovine serum supplemented with human fibrinogen. Dynamic Light Scattering (DLS), Nanoparticle Tracking Analysis (NTA), Laser Doppler Electrophoresis (LDE), and Gel Chromatography techniques have been used to assure a complete physico-chemical characterization of the nano-complexes with (LLNCs-αHER2-PC) and without (LLNCs-αHER2) the surrounding PC. In addition, cellular assays were performed to study the cellular uptake and the specific cellular-nanocarrier interactions using the SKBR3 (high expression of HER2) breast cancer cell line and human dermal fibroblasts (HDFa) (healthy cell line without expression of HER2 receptors as control), showing that the SKBR3 cell line had a higher transport rate (50-fold) than HDFa at 60 min with LLNCs-αHER2. Moreover, the SKBR3 cell line incubated with LLNCs-αHER2-PC suffered a significant reduction (40%) in the uptake. These results suggest that the formation of a PC onto LLNCs does not prevent specific cell targeting, although it does have an important influence on cell uptake.

Maslinic acid solid lipid nanoparticles as hydrophobic anticancer drug carriers: Formulation, in vitro activity and in vivo biodistribution.

Maslinic acid (MA) is a natural pentacyclic triterpenoid with inherent antitumor activity which has a very low solubility in water. MA solid lipid nanoparticles (SLNs) were prepared using Poloxamer 407 and Dicarboxylic acid-Poloxamer 407 as surfactants. Both MA SLNs are monodisperse, with sizes around 130 nm, and stable. Curcumin has been encapsulated in both types of nanoparticles without altering their colloidal properties. Moreover, SLNs greatly improve the solubility of MA and Curcumin. The cytotoxicity of MA and SLNs has been evaluated in BxPC3 human pancreatic cancer cells, MCF7 human breast cancer cells, and in a human fibroblast primary cell line. MA shows higher cytotoxic effect in BxPC3 and MCF7 cancer cells than in human primary fibroblasts. Nile Red loaded MA SLNs are quickly uptaken by BxPC3 and MCF7 cells, and show different cytoplasmic distributions depending on the cellular line. The oral or intravenous administration of MA SLNs in mice does not report any toxic effect, and the intravenous administration of fluorescent MA SLNs shows a homogeneous distribution in mice, without site-specific accumulation. Results suggest the great potential of MA SLNs as nanocarriers of anticancer drugs and as promising targeted theranostic nanodevices.

Lipid-core nanoparticles: Classification, preparation methods, routes of administration and recent advances in cancer treatment.

Nanotechnological drug delivery platforms represent a new paradigm for cancer therapeutics as they improve the pharmacokinetic profile and distribution of chemotherapeutic agents over conventional formulations. Among nanoparticles, lipid-based nanoplatforms possessing a lipid core, that is, lipid-core nanoparticles (LCNPs), have gained increasing interest due to lipid properties such as high solubilizing potential, versatility, biocompatibility, and biodegradability. However, due to the wide spectrum of morphologies and types of LCNPs, there is a lack of consensus regarding their terminology and classification. According to the current state-of-the-art in this critical review, LCNPs are defined and classified based on the state of their lipidic components in liquid lipid nanoparticles (LLNs). These include lipid nanoemulsions (LNEs) and lipid nanocapsules (LNCs), solid lipid nanoparticles (SLNs) and nanostructured lipid nanocarriers (NLCs). In addition, we present a comprehensive and comparative description of the methods employed for their preparation, routes of administration and the fundamental role of physicochemical properties of LCNPs for efficient antitumoral drug-delivery application. Market available LCNPs, clinical trials and preclinical in vivo studies of promising LCNPs as potential treatments for different cancer pathologies are summarized.