A new paradigm for lymph node regeneration via cell-based drug delivery systems

Cell-based drug delivery systems are new strategies in targeted delivery in which cells or cell-membrane-derived systems are used as carriers and release their cargo in a controlled manner. Recently, great attention has been directed to cells as carrier systems for treating several diseases. There are various challenges in the development of cell-based drug delivery systems. The prediction of the properties of these platforms is a prerequisite step in their development to reduce undesirable effects. Integrating nanotechnology and artificial intelligence leads to more innovative technologies. Artificial intelligence quickly mines data and makes decisions more quickly and accurately. Machine learning as a subset of the broader artificial intelligence has been used in nanomedicine to design safer nanomaterials. Here, how challenges of developing cell-based drug delivery systems can be solved with potential predictive models of artificial intelligence and machine learning is portrayed. The most famous cell-based drug delivery systems and their challenges are described. Last but not least, artificial intelligence and most of its types used in nanomedicine are highlighted. The present Review has shown the challenges of developing cells or their derivatives as carriers and how they can be used with potential predictive models of artificial intelligence and machine learning.

Cell-based drug delivery systems have shown tremendous advantages in cancer treatment due to their distinctive properties. For instance, delivery of therapeutics using tumor-tropic cells like neutrophils, lymphocytes and mesenchymal stem cells can achieve specific tumor targeting due to the “Trojan Horse” effect. Other circulatory cells like erythrocytes and platelets can greatly improve the circulation time of nanoparticles due to their innate long circulation property. Adipocytes, especially cancer-associated adipocytes, play key roles in tumor development and metabolism, therefore, adipocytes are regarded as promising bio-derived nanoplatforms for anticancer targeted drug delivery. Nanomaterials are important participants in cell-based drug delivery because of their unique physicochemical characteristics. Therefore, the integration of various nanomaterials with different cell types will endow the constructed delivery systems with many attractive properties due to the merits of both. In this review, a number of strategies based on nanomaterial-involved cell-mediated drug delivery systems for cancer treatment will be summarized. This review discusses how nanomaterials can be a benefit to cell-based therapies and how cell-derived carriers overcome the limitations of nanomaterials, which highlights recent advancements and specific biomedical applications based on nanomaterial-mediated, cell-based drug delivery systems.

Significant progress has been made in developing cell-based drug delivery systems that utilize the intrinsic biological properties of various cell types—erythrocytes, leukocytes, platelets, stem cells, and even spermatozoa—to improve drug targeting, bioavailability, and biocompatibility. This review presents an integrative analysis of the latest advances in cell-based drug delivery systems, focusing on their design, pharmacokinetics, cellular interactions, and therapeutic potential. We specifically focus on hybrid microrobots and membrane-coated nanocarriers as emerging biohybrid platforms. Despite these advances, translation to the clinical phase remains constrained by persistent limitations, such as immune clearance, loss of membrane integrity during cargo loading, limited tissue penetration of carrier cells, and manufacturing challenges. Finally, we highlight future directions, including CAR-cell combinations and artificial cell engineering, that promise to expand the clinical utility of cell-based drug delivery systems in oncology, infectious diseases, and regenerative medicine.

Nanotechnology in cancer therapy has significantly advanced treatment precision, effectiveness, and safety, improving patient outcomes and personalized care. Engineered smart nanoparticles and cell-based therapies are designed to target tumor cells, precisely sensing the tumor microenvironment (TME) and sparing normal cells. These nanoparticles enhance drug accumulation in tumors by solubilizing insoluble compounds or preventing their degradation, and they can also overcome therapy resistance and deliver multiple drugs simultaneously. Despite these benefits, challenges remain in patient-specific responses and regulatory approvals for cell-based or nanoparticle therapies. Cell-based drug delivery systems (DDSs) that primarily utilize the immune-recognition principle between ligands and receptors have shown promise in selectively targeting and destroying cancer cells. This review aims to provide a comprehensive overview of various nanoparticle and cell-based drug delivery system types used in cancer research. It covers approved and experimental nanoparticle therapies, including liposomes, micelles, protein-based and polymeric nanoparticles, as well as cell-based DDSs like macrophages, T-lymphocytes, dendritic cells, viruses, bacterial ghosts, minicells, SimCells, and outer membrane vesicles (OMVs). The review also explains the role of TME and its impact on developing smart DDSs in combination therapies and integrating nanoparticles with cell-based systems for targeting cancer cells. By detailing DDSs at different stages of development, from laboratory research to clinical trials and approved treatments, this review provides the latest insights and a collection of valuable citations of the innovative strategies that can be improved for the precise treatment of cancer.

Nanoparticle-based drug delivery systems have been designed to treat various diseases. However, many problems remain, such as inadequate tumor targeting and poor therapeutic outcomes. To overcome these obstacles, cell-based drug delivery systems have been developed. Candidates for cell-mediated drug delivery include blood cells, immune cells, and stem cells with innate tumor tropism and low immunogenicity; they act as a disguise to deliver the therapeutic payload. In drug delivery systems, therapeutic agents are encapsulated intracellularly or attached to the surface of the plasma membrane and transported to the desired site. Here, we review the pros and cons of cell-based therapies and discuss their homing mechanisms in the tumor microenvironment. In addition, different strategies to load therapeutic agents inside or on the surface of circulating cells and the current applications for a wide range of disease treatments are summarized.

Cell-based drug delivery systems and their in vivo fate

Anticancer drugs and diagnostics can be transported in nanoscale vesicles that provide a flexible platform. A hybrid nanoparticle, a nano assembly made up of many types of nanostructures, has the greatest potential to perform these two activities simultaneously. Nanomedicine has shown the promise of vesicular carriers based on lipopolymersomes, lipid peptides, and metallic hybrid nano-vesicle systems. However, there are significant limitations that hinder the clinical implementation of these systems at the commercial scale, such as low productivity, high energy consumption, expensive setup, long process durations, and the current cancer therapies described in this article. Combinatorial hybrid systems can be used to reduce the above limitations. A greater therapeutic index and improved clinical results are possible with hybrid nanovesicular systems, which integrate the benefits of many carriers into a single structure. Due to their unique properties, cell-based drug delivery systems have shown tremendous benefits in the treatment of cancer. Nanoparticles (NPs) can benefit significantly from the properties of erythrocytes and platelets, which are part of the circulatory cells and circulate for a long time. Due to their unique physicochemical properties, nanomaterials play an essential role in cell-based drug delivery. Combining the advantages of different nanomaterials and cell types gives the resulting delivery systems a wide range of desirable properties. NPs are nextgeneration core-shell nanostructures that combine a lipid shell with a polymer core. The fabrication of lipid-polymer hybrid NPs has recently undergone a fundamental shift, moving from a two-step to a one-step technique based on the joint self-assembly of polymers and lipids. Oncologists are particularly interested in this method as a combinatorial drug delivery platform because of its two-in-one structure. This article addresses various preparative methods for the preparation of hybrid nano-vesicular systems. It also discusses the cellular mechanism of hybrid nano-vesicular systems and describes the thorough knowledge of various hybrid vesicular systems.

Engineered cellular drug delivery: Strategies and applications

Chapter 2 - Erythrocytes modified (coated) gold nanoparticles for effective drug delivery

Microparticle-loaded neonatal porcine Sertoli cells for cell-based therapeutic and drug delivery system.

In vitro analysis of genome-engineered muscle-derived stem cells for autoregulated anti-inflammatory and antifibrotic activity.

Diseases of deficient or subnormal metabolic or secretory cell function, such as diabetes mellitus, are on the increase due to an aging population and increased incidence of metabolic syndrome. At present, the only means of reversal is allograft transplantation. However, the amount of tissue available for transplantation precludes this as a viable option for treating the majority of the patient population. In addition, the required immunosuppressive drug regimen is associated with many long-term side effects. The use of microencapsulation cell therapy to transplant foreign cells or tissue for providing site-specific and dynamic delivery of cell-synthesized molecules is an attractive alternative treatment to replace the lost function in the host tissue. In microencapsulation, the transplant material is covered with a semi-permeable membrane prior to transplantation to shield it from the immune system of recipients. The membrane allows for the transportation of nutrients and therapeutic agents but is relatively impermeable to the larger molecules and cells of the recipient’s immune system. This technique avoids the requirement for immunosuppressive drugs, enlarges the amount of available transplant material and provides long-term and continuous drug delivery to sites that are difficult to access in the body. Microencapsulation of cell spheroids in an immunoselective, highly biocompatible, biomembrane such as alginate/polycation/alginate (APA) offers a way to create viable implantation options. Traditionally the encapsulation process has been achieved through the injection/extrusion of alginate/cell mixtures into a calcium chloride solution to produce calcium alginate capsules around the cells. While an immuno-isolating membrane can be established around the cells, the microcapsules generated have substantial dead space leading to an unnecessarily large transplant volume. A novel alternative is explored in this thesis, in which a two-phase emulsion process is used to produce thin coherent alginate membranes around cell spheroids. A thorough investigation has been used to establish the emulsion process parameters that are critical to the formation of a coherent alginate coat both on a model spheroid system of polymer beads and subsequently on cell spheroids. Optical and Fluorescence microscopy are used to assess the morphology and coherence of the calcium alginate/poly-L-ornithine/alginate (APA) capsules produced. The developed coherent APA microcapsule can provide an immunoselective and highly biocompatible membrane for cellular or tissue transplantation. However, this technique is not applicable for xenograft transplantation, as small peptides and other foreign molecules released from the xenogenic transplant material can diffuse through the coherent microcapsules and trigger the indirect response of the host immune system. This thesis explored a novel approach in which alginate is biotinylated using carbodiimide crosslinking chemistry to facilitate subsequent immobilisation of biomolecules to further augment the biofunctionality of the microcapsules via a streptavidin-biotin conjugation. A thorough investigation has been conducted to optimize and characterize alginate biotinylation via carbodiimide chemistry by a 4’-hydroxyazobenzene-2-carboxylic acid (HABA) based assay and by ATR-FTIR, H-NMR and XPS. To minimize the formation of by-product, a theoretical 40% activation of the carboxylic group on the alginate was employed to manufacture an optimal modification of ~10% biotinylated alginate. Confocal fluorescence microscopy was used to assess the conjugation of streptavidin and assembly of antibodies on the microcapsules. Local immunosuppressive capacity was assimilated on the APA microcapsules by binding of anti-tumor necrosis factor-alpha (TNF-α) antibodies via streptavidin¬biotin conjugation, shown from the clear reduction of TNF-α in in-vitro medium. Conventional alginate/poly-L-ornithine (AP) membranes fail in long-term transplantations of immortal cell lines. Continuous cell proliferation inside the microcapsule causes rapid rupture of the membranes causing immediate immune rejection. This restricts the applicability of immortal cell lines for the development of cell-based drug delivery systems. This thesis examines a novel layer-by-layer (LbL) membrane using polystyrene sulfonate and polyallylamine hydrochloride (PSS/PAH) on top of the coherent AP membrane. Assembly of the LbL membrane was followed by electrophoresis, and the surface morphologies and structure were characterized and examined by cryo-scanning electron microscope (Cryo-SEM) and transmission electron microscopy (TEM). Unlike the standard AP membrane, the LbL multilayer membrane withstood the internal pressure generated by continuous cell proliferation of microencapsulated HEK-293 and Min-6 cells. The new membrane did not affect insulin secretion and diffusion by the Min-6 cell line. This thesis demonstrates that using the two-phase emulsion method, coherent alginate microcapsule can be readily and controllably manufactured for the microencapsulation of a cell spheroid. This coherent alginate microcapsule can be further enhanced with biofunctional and mechanical argumentation on the alginate/PLO membrane, enabling it as a robust cell-based drug delivery system suitable for a variety of medical applications.

Transferrin-modified bone marrow mesenchymal stem cell co-loaded with phthalocyanine and perfluorohexane for targeted antitumor therapy.

Drug delivery systems aim at improving drug transport efficiency and therapeutic efficacy by rational design, and current research on conventional delivery systems brings new developments for disease treatment. Recently, studies on cell-based drug delivery systems are rapidly emerging, which shows great advantages in comparison to conventional drug delivery system. The system uses cells as carriers to delivery conventional drugs or nanomedicines and shows good biocompatibility and enhanced targeting efficiency, beneficial from self component and its physiological function. The construction methodology of cell-based carrier determines the effect on the physiological functions of transporting cell and affects its clinical application. There are different strategies to prepare cell-based carrier, such as direct internalization or surface conjugation of drugs or drug loaded materials. Thus, it is necessary to fully understand the advantages and disadvantages of different strategies for constructing cell-based carrier and then to seek the appropriate construction methodology for achieving better therapeutic results based on disease characterization. We here summarize the application of different types of cell-based carriers reported in recent years and further discuss their applications in disease therapy and the dilemmas faced in clinical translation. We hope that this summary can accelerate the process of clinical translation by promoting the technology development of cell-based carrier.

Photodynamic therapy (PDT) is a multidisciplinary area, which involves photophysics and photochemical sciences and plays an important role in cancer diagnosis and treatment. PDT involves a photo-activable drug called photosensitizer (PS), a specific wavelength of light and cellular compounds to produce toxic oxygen species in a much-localized way to destroy malignant tumors. Despite the various benefits of PDT, some PS-related limitations hinder its use as an ideal treatment option for cancer. To address these limitations (e.g., poor bioavailability, weak permeability, hydrophobicity, and aggregation), lipid-based and vesicular drug delivery systems have been employed. These carrier systems possess the ability to enhance the bioavailability, permeability, and solubility of the drug. Furthermore, they tend to load hydrophobic and lipophilic compounds and can be employed for an efficient and targeted drug delivery. The purpose of this review is to highlight the precise idea of PDT, the limitations of PDT related to PS, and the application of lipidic and tocosomal carriers in PDT for the treatment of various types of cancers. Liposomes, nanoliposomes, solid lipid nanoparticles, vesicular phospholipid gels, exosomes, transferosomes, and tocosomes are presented as commonly-employed vesicular drug carriers. Moreover, the amalgamation of cell-based drug delivery systems (CBDDS) with PDT holds considerable potential as an encouraging avenue in cancer treatment, especially in the context of immunotherapy.