Cell-based Delivery Research Articles

Covalent and Noncovalent Conjugation of Degradable Polymer Nanoparticles to T Lymphocytes.

Cells are attractive as carriers that can help to enhance control over the biodistribution of polymer nanomedicines. One strategy to use cells as carriers is based on the cell surface immobilization of the nanoparticle cargo. While a range of strategies can be used to immobilize nanoparticles on cell surfaces, only limited effort has been made to investigate the effect of these surface modification chemistries on cell viability and functional properties. This study has explored seven different approaches for the immobilization of poly(lactic acid) (PLA) nanoparticles on the surface of two different T lymphocyte cell lines. The cell lines used were human Jurkat T cells and CD4+ TEM cells. The latter cells possess blood-brain barrier (BBB) migratory properties and are attractive for the development of cell-based delivery systems to the central nervous system (CNS). PLA nanoparticles were immobilized either via covalent active ester-amine, azide-alkyne cycloaddition, and thiol-maleimide coupling, or via noncovalent approaches that use lectin-carbohydrate, electrostatic, or biotin-NeutrAvidin interactions. The cell surface immobilization of the nanoparticles was monitored with flow cytometry and confocal microscopy. By tuning the initial nanoparticle/cell ratio, T cells can be decorated with up to ∼185 nanoparticles/cell as determined by confocal microscopy. The functional properties of the nanoparticle-decorated cells were assessed by evaluating their binding to ICAM-1, a key protein involved in the adhesion of CD4+ TEM cells to the BBB endothelium, as well as in a two-chamber model in vitro BBB migration assay. It was found that the migratory behavior of CD4+ TEM cells carrying carboxylic acid-, biotin-, or Wheat germ agglutinin (WGA)-functionalized nanoparticles was not affected by the presence of the nanoparticle payload. In contrast, however, for cells decorated with maleimide-functionalized nanoparticles, a reduction in the number of migratory cells compared to the nonmodified control cells was observed. Investigating and understanding the impact of nanoparticle-cell surface conjugation chemistries on the viability and properties of cells is important to further improve the design of cell-based nanoparticle delivery systems. The results of this study present a first step in this direction and provide first guidelines for the surface modification of T cells, in particular in view of their possible use for drug delivery to the CNS.

A Genetically Modified Skin Graft for Treating Alcohol Use Disorder and/or Polysubstance Abuse With Cocaine.

Alcohol use disorder (AUD) is one of the foremost public health problems. Alcohol is also frequently co-abused with cocaine. There is a huge unmet need for the treatment of AUD and/or cocaine co-abuse. We have developed and used a skin stem cell-based gene delivery platform and found that production of the glucagon-like peptide-1 (GLP1) from the grafted genetically modified skin reduced development and reinstatement of alcohol-induced drug-taking and seeking, voluntary oral alcohol consumption and alcohol-induced increase in dopamine (DA) levels in the nucleus accumbens (NAc). Moreover, we have developed a novel co-grafting procedure for both modified human butyrylcholinesterase (hBChE)- and GLP1-expressing cells. Skin grafts-derived hBChE and GLP1 reduced acquisition of drug-taking and toxicity induced by concurrent alcohol and cocaine injections. These results imply that gene delivery through skin transplants may add a new option to treat drug abuse and co-abuse.

Primary Macrophage-Based Microrobots: An Effective Tumor Therapy In Vivo by Dual-Targeting Function and Near-Infrared-Triggered Drug Release.

Macrophages (MΦs) have the capability to sense chemotactic cues and to home tumors, therefore presenting a great approach to engineer these cells to deliver therapeutic agents to treat diseases. However, current cell-based drug delivery systems usually use commercial cell lines that may elicit an immune response when injected into a host animal. Furthermore, premature off-target drug release also remains an enormous challenge. Here, we isolated and differentiated MΦs from the spleens of BALB/c mice and developed dual-targeting MΦ-based microrobots, regulated by chemotaxis and an external magnetic field, and had a precise spatiotemporal controlled drug release at the tumor sites in response to the NIR laser irradiation. These microrobots were prepared by coloading citric acid (CA)-coated superparamagnetic nanoparticles (MNPs) and doxorubicin (DOX)-containing thermosensitive nanoliposomes (TSLPs) into the MΦs. CA-MNPs promoted a magnetic targeting function to the microrobots and also permitted photothermal heating in response to the NIR irradiation, triggering drug release from TSLPs. In vitro experiments showed that the microrobots effectively infiltrated tumors in 3D breast cancer tumor spheroids, particularly in the presence of the magnetic field, and effectively induced tumor cell death, further enhanced by the NIR laser irradiation. In vivo experiments confirmed that the application of the magnetic field and NIR laser could markedly inhibit the growth of tumors with a subtherapeutic dose of DOX and a single injection of the microrobots. In summary, the study proposes a strategy for the effective anticancer treatment using the developed microrobots.

Cell-based drug delivery harnesses inflammatory and autoimmune responses in neurodegeneration.

Cell-based drug delivery harnesses inflammatory and autoimmune responses in neurodegeneration.

Reducing alcohol and/or cocaine-induced reward and toxicity via an epidermal stem cell-based gene delivery platform

Alcohol use disorder (AUD) is one of the foremost public health problems. Alcohol is also frequently co-abused with cocaine. There is a huge unmet need for the treatment of AUD and/or cocaine co-abuse. We recently demonstrated that skin grafts generated from mouse epidermal stem cells that had been engineered by CRISPR-mediated genome editing could be transplanted onto mice as a gene delivery platform. Here, we show that expression of the glucagon-like peptide-1 (GLP1) gene delivered by epidermal stem cells attenuated development and reinstatement of alcohol-induced drug-taking and seeking as well as voluntary oral alcohol consumption. GLP1 derived from the skin grafts decreased alcohol-induced increase in dopamine levels in the nucleus accumbens. In exploring the potential of this platform in reducing concurrent use of drugs, we developed a novel co-grafting procedure for both modified human butyrylcholinesterase (hBChE)- and GLP1-expressing cells. Epidermal stem cell-derived hBChE and GLP1 reduced acquisition of drug-taking and toxicity induced by alcohol and cocaine co-administration. These results imply that cutaneous gene delivery through skin transplants may add a new option to treat drug abuse and co-abuse.

Organophosphate detoxification by membrane-engineered red blood cells

Biotherapeutics have achieved global economic success due to their high specificity towards their drug targets, providing exceptional safety and efficiency. The ongoing shift away from small molecule drugs towards biotherapeutics heightens the need to further improve the pharmacokinetics of these biological drugs. Three pervasive obstacles that limit the therapeutic capacity of biotherapeutics are proteolytic degradation, circulating half-life, and the development of anti-drug antibodies. These challenges can culminate in limited efficiency and consequently warrant the need for higher drug doses and more frequent administration. We have explored the coupling of biotherapeutics to long-lived and biocompatible red blood cells (RBCs) to address limited pharmacokinetics. Butyrylcholinesterase (BChE), for example, provides prophylactic protection against organophosphate nerve agents (OPNAs), yet the short circulation life of the drug requires extraordinary doses. Herein, we report the rapid and tunable chemical engineering of BChE to RBC membranes to create a cell-based delivery system that retains the enzyme activity and enhances stability. In a three-step process that first pre-modifies BChE with a cell-reactive polymer chain, primes the cells for engineering, and then grafts the conjugates to the cells, we attached over 2 million BChE molecules to the surface of each RBC without diminishing the bioscavenging capacity of the enzyme. Critically, this membrane-engineering approach was cell-tolerated with minimal hemolysis observed. These results provide strong evidence for the ability of engineered RBCs to serve as an enhanced biotherapeutic delivery vehicle. Statement of SignificanceOrganophosphate nerve agents (OPNAs) are one of the most lethal forms of chemical warfare. After exposure to OPNAs, a patient is given life-saving therapeutics, such as atropine and oxime. However, these drugs are limited, and the patient can still suffer from irreparable injuries. Given the toxicity of OPNAs, access to a prophylactic is vital. We have created an enhanced delivery system for prophylactic butyrylcholinesterase (BChE) by engineering this biotherapeutic to the red blood cell (RBC) surface. In three simple steps that first pre-modifies BChE with a cell-reactive polymer, primes the cells for engineering, and then grafts the conjugates to the cells, we attached over 2 million BChE molecules to a single RBC while retaining the enzyme's activity and enhancing its stability.

Modification of human monocytes and macrophages by magnetic nanoparticles in vitro for cell-based delivery

The aim of the study was to develop a method for the modification of human monocytes/macrophages by iron oxide magnetic nanoparticles in vitro . Materials and methods . Iron oxide magnetic nanoparticles were obtained by a co-precipitation method and coated with a thin SiO 2 layer and polyethylene glycol 3000. Murine macrophage-like cell line RAW 264.7, primary human monocytes and macrophages were incubated with magnetic nanoparticles for 1–24 hours. The efficiency of cellular uptake of nanoparticles was measured using a ferrozine-based method and microcopy with Perls’ Prussian blue staining. The cell viability was tested by fluorescent flow cytometry using SYTOX Green. Results. Incubation of RAW264.7 cell, human monocytes and macrophages with magnetic nanoparticles at a concentration ˃ 5 µg/mL on a rotator for 1 hour at 37 °С provides the loading of nanoparticles into > 99% of cells. The magnetic nanoparticles have no adverse effect on the cell viability. The RAW264.7 cells modified with nanoparticles showed no change in migration activity. The efficiency of the nanoparticle uptake by macrophages was ˃50 pkg (Fe)/cell. Conclusion . According to the proposed method, macrophages loaded with magnetic nanoparticles have proved viable, they retain the ability to migrate, and therefore can be used as cell-based delivery systems for tumor diagnostic and therapy.

A cell-based drug delivery platform for treating central nervous system inflammation.

Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases. KEY MESSAGES: MSCs can spontaneously take up the ATP-competitive kinase inhibitor Ro-31-8425. Ro-31-8425-loaded MSCs gradually release Ro-31-8425 and exhibit sustained suppression of T cells. Ro-31-8425-loaded MSCs have more sustained serum levels of Ro-31-8425 than free Ro-31-8425. Ro-31-8425-loaded MSCs are more effective than MSCs and free Ro-31-8425 for EAE therapy.

From blood to brain: blood cell-based biomimetic drug delivery systems

Brain drug delivery remains a major difficulty for several challenges including the blood–brain barrier, lesion spot targeting, and stability during circulation. Blood cells including erythrocytes, platelets, and various subpopulations of leukocytes have distinct features such as long-circulation, natural targeting, and chemotaxis. The development of biomimetic drug delivery systems based on blood cells for brain drug delivery is growing fast by using living cells, membrane coating nanotechnology, or cell membrane-derived nanovesicles. Blood cell-based vehicles are superior delivery systems for their engineering feasibility and versatile delivery ability of chemicals, proteins, and all kinds of nanoparticles. Here, we focus on advances of blood cell-based biomimetic carriers for from blood to brain drug delivery and discuss their translational challenges in the future.

Neutrophils mediated multistage nanoparticle delivery for prompting tumor photothermal therapy

BackgroundNeutrophil-based drug delivery system possesses excellent advantages in targeting at tumour because neutrophils are easily recruited by chemotactic factor in tumor microenvironment. Herein, we developed a novel tactic of multistage neutrophils-based nanoparticle delivery system for promoting photothermal therapy (PTT) of lung cancer.ResultsAu nanorod (AuNR) was successfully modified with bovine serum albumin (AuNRB) and further conjugated with RGD (AuNRBR), followed by neutrophil internalisation to obtain neutrophils-based delivery system (AuNRBR/N). The engineered neutrophils efficiently migrated across the epithelial cells due to inflammatory signal. They exhibited better toxicity against Lewis cells with laser irradiation in vitro. Moreover, AuNRBR/N showed significantly more targetability to tumour tissue compared with cell carrier-free AuNRBR, as demonstrated in Lewis tumour-bearing mice. The enhanced tumour homing efficiency of AuNRBR/N together with subsequently released AuNRBR from the neutrophils was favourable for further deep tissue diffusion and contributed to the inhibition of the tumour growth in PTT and improved survival rate (over 120 days).ConclusionsOverall results illustrated that the design of cell-based nanoparticle delivery system for PTT of cancer is promising.

Update on newer approaches to prevent or treat COVID-19 infection: What we all need the most right now!!

COVID-19 convalescent plasma (CCP) therapy involves the use of circulating antibodies administration from recovered COVID 19 patients as a practical strategy to provide immediate passive immunity in susceptible recipients in need. Global concern over the potential for “second” or “third” waves of infection to occur before effective vaccines or drug therapies are available has many looking at other biological sources for large-scale production of neutralizing SARS-CoV-2 antibodies. This report summarizes some of the novel strategies for developing alternative safe sources of therapeutic autologous antibodies from COVID ‐19 infected patients, and provides some original thoughts on how to rapidly implement a safe passive immunity in those COVID-19 patients who are most in need of intervention. COVID-19 antibodies can be isolated or delivered using a number of other techniques including: plasmapheresis, plasma cryoprecipitate reduced (cryosupernatant), antibody hyperconcentrates and advanced cell-based delivery systems. While these proposed technological options may, in some cases, be theoretical, the growing concern over the rapid spread of the SARS-CoV-2 virus has prompted many to pursue innovative and creative solutions to reduce the mortality and morbidity resulting from the current global pandemic. A comparative analysis of various strategies currently in use deserved exploring and this highlighted separately as the essential part of this concise theme.

Fluorescence-Based and Fluorescent Label-Free Characterization of Polymer Nanoparticle Decorated T Cells.

Cells are attractive carriers for the transport and delivery of nanoparticulate cargo. The use of cell-based carriers allows one to enhance control over the biodistribution of drug-loaded polymers and polymer nanoparticles. One key element in the development of cell-based delivery systems is the loading of the cell-based carrier with the nanoparticle cargo, which can be achieved either by internalization of the payload or by immobilization on the cell surface. The surface modification of cells with nanoparticles or the internalization of nanoparticles by cells is usually monitored with fluorescence-based techniques, such as flow cytometry and confocal microscopy. In spite of the widespread use of these techniques, the use of fluorescent labels also poses some risks and has several drawbacks. Fluorescent dyes may bleach, or leach from, the nanoparticles or alter the physicochemical properties of nanoparticles and their interactions with and uptake by cells. Using poly(d,l-lactic acid) nanoparticles that are loaded with Coumarin 6, BODIPY 493/503, or DiO dyes as a model system, this paper demonstrates that the use of physically entrapped fluorescent labels can lead to false negative or erroneous results. The use of nanoparticles that contain covalently tethered fluorescent dyes instead was found to provide a robust approach to monitor cell surface conjugation reactions and to quantitatively analyze nanoparticle-decorated cells. Finally, it is shown that optical diffraction tomography is an attractive, alternative technique for the characterization of nanoparticle-decorated cells, which obviates the need for fluorescent labels.

Genetically modified macrophages accomplish targeted gene delivery to the inflamed brain in transgenic Parkin Q311X(A) mice: importance of administration routes

Cell-based drug delivery systems have generated an increasing interest in recent years. We previously demonstrated that systemically administered macrophages deliver therapeutics to CNS, including glial cell line-derived neurotrophic factor (GDNF), and produce potent effects in Parkinson’s disease (PD) mouse models. Herein, we report fundamental changes in biodistribution and brain bioavailability of macrophage-based formulations upon different routes of administration: intravenous, intraperitoneal, or intrathecal injections. The brain accumulation of adoptively transferred macrophages was evaluated by various imaging methods in transgenic Parkin Q311(X)A mice and compared with those in healthy wild type littermates. Neuroinflammation manifested in PD mice warranted targeting macrophages to the brain for each route of administration. The maximum amount of cell-carriers in the brain, up to 8.1% ID/g, was recorded followed a single intrathecal injection. GDNF-transfected macrophages administered through intrathecal route provided significant increases of GDNF levels in different brain sub-regions, including midbrain, cerebellum, frontal cortex, and pons. No significant offsite toxicity of the cell-based formulations in mouse brain and peripheral organs was observed. Overall, intrathecal injection appeared to be the optimal administration route for genetically modified macrophages, which accomplished targeted gene delivery, and significant expression of reporter and therapeutic genes in the brain.

Mesenchymal stem cells engineered by modified polyethylenimine polymer for targeted cancer gene therapy, in vitro and in vivo.

Cell-based delivery system is a promising strategy to protect therapeutic agents from the immune system and provide targeted delivery. Mesenchymal stem cells (MSCs) have recently been introduced as an encouraging vehicle in cell-based gene therapy due to their unique features including tumor-tropic property and migratory ability. However, gene transfer into MSCs is limited due to low efficiency and cytotoxicity of carriers. In this study, we designed a novel delivery system based on polyethylenimine (PEI25 ) to improve these features of carrier and transfect plasmid encoding TRAIL to MSCs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand of TNF family with selective effect on cancerous cells. Then, death induction and migration ability of TRAIL-expressing MSCs was studied in melanoma cells. The effect of engineered-MSCs as an antitumor vehicle was also investigated in mice bearing melanoma cells. Our findings indicated that heterocyclic amine derivative of PEI25 showed significant improvement in MSCs viability determined by MTT assay and gene expression using fluorescent microscopy, flow cytometry, and Western blot analysis. We observed that engineered-MSCs could migrate toward and induce cell death in B16F0 cells in vitro. The single administration of TRAIL-expressing MSCs could delay tumor appearance and efficiently reduce tumor weights. Hematoxylin and eosin staining of tumor sections revealed extensive neoplastic cells necrosis. Furthermore, engineered-MSCs could migrate and localize to tumors sites within 5 days. Our results indicated that MSCs engineered by modified-PEI/TRAIL complexes could be considered as a promising cellular vehicle for targeted tumor suppression.

Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours.

Drug delivery is one of the major challenges in the treatment of central nervous system disorders. The brain needs to be protected from harmful agents, which are done by the capillary network, the so-called blood-brain barrier (BBB). This protective guard also prevents the delivery of therapeutic agents to the brain and limits the effectiveness of treatment. For this reason, various strategies have been explored by scientists for overcoming the BBB from disruption of the BBB to targeted delivery of nanoparticles (NPs) and cells and immunotherapy. In this review, different promising brain drug delivery strategies including disruption of tight junctions in the BBB, enhanced transcellular transport by peptide-based delivery, local delivery strategies, NP delivery, and cell-based delivery have been fully discussed.

Neural Stem Cells Improve the Delivery of Oncolytic Chimeric Orthopoxvirus in a Metastatic Ovarian Cancer Model

Oncolytic virotherapy represents a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance, which reduces viral delivery to the tumor. Patient-derived mesenchymal stem cells that home to tumors have been used as viral delivery tools, but variability associated with autologous cell isolations limits the clinical applicability of this approach. We previously developed an allogeneic, clonal neural stem cell (NSC) line (HB1.F3.CD21) that can be used to deliver viral cargo. Here, we demonstrate that this NSC line can improve the delivery of a thymidine kinase gene-deficient conditionally replication-competent orthopoxvirus, CF33, in a preclinical cisplatin-resistant peritoneal ovarian metastases model. Overall, our findings provide the basis for using off-the-shelf allogeneic cell-based delivery platforms for oncolytic viruses, thus providing a more efficient delivery alternative compared with the free virus administration approach.

Stem Cell-Based Delivery of Gold/Chlorin e6 Nanocomplexes for Combined Photothermal and Photodynamic Therapy

Combining photothermal and photodynamic modalities has shown encouraging therapeutic efficacy against various malignant cancers. Developing a delivery method for targeting and penetrating tumors is still a major focus for advancing this therapeutic approach. Herein, we report a novel strategy involving the utilization of stem cells as a live carrier to codeliver photothermal and photodynamic agents for cancer therapy. To this end, a novel gold nanorod (AuNR)-PEG-PEI (APP)/chlorin e6 (Ce6)-loaded adipose-derived stem cell (ADSC) system is proposed in which AuNRs and Ce6 act as the photothermal and photodynamic agents, respectively. To integrate with stem cells, the APP/Ce6 nanocomplexes exhibit advantages of low drug leakage, low cytotoxicity, efficient cellular uptake, and redox-responsive release. After loading of APP/Ce6 nanocomplexes, the ADSCs still maintained good tumor tropism and were capable of penetrating into the tumor spheroids. The photothermal effect induced by exposure to near-infrared light irradiation at 808 nm promoted the release of Ce6 from the stem cells into the surroundings and hence increased its availability to treat cancer cells. APP/Ce6-loaded ADSCs exerted effective dose-dependent in vitro anticancer activities via anticipated photothermal and photodynamic effects. In a murine CT26 colon cancer model, APP/Ce6 delivered by ADSCs resulted in superior tumor suppression compared to other delivery strategies. It was also noted that in vivo applications of APP/Ce6-loaded ADSCs did not induce noticeable detrimental effects on normal tissues/organs.

Enhancement of the therapeutic effects of oncolytic vaccinia virus by using autologous and allogeneic cell-based delivery platforms.

e15271 Background: Clinical trials with oncolytic viruses for cancer treatment have shown limited efficacy due to viruses’ rapid clearance by patients’ innate and adaptive immune systems. In a recent first-in-human clinical trial, we confirmed the safety and feasibility of our approach to enhance oncolytic vaccinia virus (OVV) delivery and improve tumor targeting by utilizing an autologous cell-based cell delivery system (auto-OVV). We also developed an allogeneic cell-based platform (SuperNova1c - SNV1c) aiming to protect and potentiate OVV’s antitumor effects in large patient populations. Methods: We evaluated the immunomodulatory potential of auto-OVV by an extensive time-course analysis of cytokines in patients’ plasma (Luminex profiling) and peripheral blood immune cells (flow cytometry). We also analyzed the ability of SNV1c to protect the OVV from antibody/complement inactivation in vitro and in vivo following intratumoral injection in various mouse tumors. The immune cell infiltrations of the injected tumors were also analyzed. Results: Therapy with auto-OVV induced a coordinated activation of cytokine, T cell and NK responses in patients as early as 1 day, peaking around 1-week and lasting for up to 1-month post treatment. Effective OVV amplification in cancer patients correlated with significant changes of multiple innate and adaptive immune parameters. Patient stratification into groups with transient versus persistent viral DNA was linked to opposing and mutually exclusive patterns of robust activation of NK versus T cell responses, respectively. SNV1c showed significantly enhanced protection of OVV in vitro and led to statistically significant tumor growth inhibition as compared to control non-treated tumors or to naked OVV-treated tumors. Importantly, local administration of SNV1c induced systemic therapeutic effects. Five days after SNV1c administration, tumor infiltrating lymphocytes from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations, decreased Tregs, and improved effector to Treg ratios, associated with tumor growth inhibition at both treated and untreated tumor sites. Conclusions: This study establishes the timeline of treatment-related immunological changes and identifies potential immunological correlates associated with the OVV persistence in vivo. We also demonstrate the ability of our cell-based platforms to protect and potentiate OVV by circumventing innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy.

Adipocyte-Based Cell Therapy in Oncology: The Role of Cancer-Associated Adipocytes and Their Reinterpretation as Delivery Platforms.

Cancer-associated adipocytes have functional roles in tumor development through secreted adipocyte-derived factors and exosomes and also through metabolic symbiosis, where the malignant cells take up the lactate, fatty acids and glutamine produced by the neighboring adipocytes. Recent research has demonstrated the value of adipocytes as cell-based delivery platforms for drugs (or prodrugs), nucleic acids or loaded nanoparticles for cancer therapy. This strategy takes advantage of the biocompatibility of the delivery system, its ability to locate the tumor site and also the predisposition of cancer cells to come in functional contact with the adipocytes from the tumor microenvironment for metabolic sustenance. Also, their exosomal content can be used in the context of cancer stem cell reprogramming or as a delivery vehicle for different cargos, like non-coding nucleic acids. Moreover, the process of adipocytes isolation, processing and charging is quite straightforward, with minimal economical expenses. The present review comprehensively presents the role of adipocytes in cancer (in the context of obese and non-obese individuals), the main methods for isolation and characterization and also the current therapeutic applications of these cells as delivery platforms in the oncology sector.

Dual-engineered, “Trojanized” macrophages bio-modally eradicate tumors through biologically and photothermally deconstructing cancer cells in an on-demand, NIR-commanded, self-explosive manner

To engineer tumor-tropic cells as drug delivery vehicles is a promising strategy to improve therapeutic specificity and efficacy for cancer treatment. However, conventional genetically engineered cell-based drug delivery systems are often capable of initiating single-mode therapy, and lack precise spatiotemporal control over the release of therapeutic payloads at tumor local, thus possibly causing severe systemic toxicity. Here, the macrophages are genetically engineered to encode a non-secreted form of EGFP-TNFα fusion protein and intracellularly carry near-infrared (NIR)-responsive heat-nanogenerators (HIMs). Owing to macrophages' intrinsic tumor tropism and HIMs’ photo-responsiveness to NIR, these macrophages (HIMs@eMET) can actively accumulate at tumor sites and undergo controlled photothermolysis induced by NIR-induced HIMs-mediated photothermal effects (PTE). Such heat-induced cell explosion enables spatiotemporally controlled release of non-secreted TNFα from macrophages and effectively kills cancer cells. Importantly, in a preclinical tumor model, HIMs@eMET actively migrate to tumors where PTE and released EGFP-TNFα exhibit an enhanced antitumor effect, suppressing tumor growth and significantly prolonging animal survival without eliciting adverse side effects. Thus, this study demonstrates the potential of such dual-engineered macrophages in bi-modal cancer therapy.