Key advantages
As early as 1973, it was recognized that red blood cells can be loaded with therapeutic enzymes, in order to avoid a possible immune reaction to the enzyme or rapid degradation of the enzyme if injected directly into blood. [4] In humans, red blood cells have a half-life in circulation of 10–15 days before clearance by the lymphoreticular system and exhibit a natural tendency to absorb a variety of drugs. [5] Together, these properties allow for controlled release of pharmaceutical products over an extended time, and/or targeting of erythrocyte-destroying cells such as macrophages in the spleen or liver. One of the earliest proposed applications of EBDDS was in enzyme replacement therapy for Gaucher disease, in which lipids accumulate in spleen macrophages; the enzymes not present in this disease could thus be delivered directly to macrophages by red blood cells. [4]
Furthermore, red blood cells are not immunogenic as long as the blood type is compatible with the recipient. This property allows potentially immunogenic substances such as proteins to be safely carried through the bloodstream.
Variants
There are several variations on the concept of erythrocytes as drug carriers. In the simplest application, erythrocytes may be simply mixed with a membrane-permeable drug and allowed to equilibrate until the drug has been absorbed via dialysis. [6] [7] Alternately, a prodrug may be incubated with the erythrocytes, and enzyme activity within the cells gradually converts the prodrug to its active form, further prolonging delivery. [6] If the drug or prodrug is not membrane-permeable, membrane-permeating peptides may be added to permeabilize the plasma membrane of the erythrocytes. [3]
If the therapeutic agent of interest is a protein, it may be coupled to the surface of the erythrocyte by linking biotin to the protein and to another molecule on the erythrocyte surface, and then adding streptavidin to bridge the two. [7] Similarly, therapeutic nanoparticles may attach to or embed in the red cell membranes or glycocalyx based on the chemical and physical properties of their surface ligands. [1]
For some therapeutic proteins it is only feasible to encapsulate the protein within the red cell membrane. In these cases the red blood cells must be partially lysed under isotonic conditions in the presence of the protein to be loaded, forming re-sealed erythrocytes or erythrocyte ghosts containing the protein of interest. [4] [8]
In other applications, therapeutic nanoparticles larger than proteins but smaller than erythrocytes may be "cloaked" in red blood cell membranes in order to evade immune reaction or prolong circulation. [9] This may be accomplished by hypotonic lysis or extrusion of intact red cells, followed by re-extrusion in the presence of the nanoparticles. [10] This approach may also be used to encapsulate small molecules in vesicles made from the plasma membrane of erythrocytes, if delivery particles smaller than intact cells are desired. [3]
Applications
EBDDS have been increasingly recognized for their ability to improve performance of therapeutic agents across a broad range of clinical contexts. These systems have demonstrated utility in improving drug stability, prolonging circulation, reducing systemic toxicity, and enabling targeted delivery. As a result, they have been explored for use in cancer therapy, enzyme replacement therapy, anticoagulation, and immune modulation.
Cancer therapy
EBDDSs have been studied in oncology for their possible role in optimizing chemotherapeutic delivery and adjusting the therapeutic index of enzyme- and gene-based therapies. Encapsulation of L-asparaginase (L-ASNase) within erythrocytes (ASNase-ERY) has been one of the most advanced applications in this area. This formulation allows sustained depletion of circulating asparagine -a critical nutrient for certain leukemia cells- while shielding the enzyme from immune recognition and degradation. Clinical trials of ASNase-ERY in patients with acute lymphoblastic leukemia (ALL) and pancreatic ductal adenocarcinoma (PDAC) have demonstrated extended drug half-life, reduced hypersensitivity reactions, and improved overall survival outcomes. [11] Chemotherapeutic agents such as daunorubicin, doxorubicin, and cytosine arabinoside have also been delivered using erythrocytes. Early studies utilized whole red blood cells for drug encapsulation, as opposed to more recent developments that have focused on nanoerythrosomes and RBC membrane-coated particles. These approaches enable controlled drug release, enhanced tumor accumulation, and reduced cardiotoxicity, especially for agents like doxorubicin known to cause cumulative cardiac damage. [11]
Additionally, the fusion of erythrocyte membranes with various nano-materials has led to the creation of camouflaged nanoparticles that are capable of delivering small molecules, photodynamic/photothermal agents, siRNAs, and cancer vaccines. These systems combine the long-circulating properties of erythrocytes with the multifunctionality of nanoparticles, making them good candidates for both treatment and imaging applications in solid tumors. [8; Rao et al. (2016)]
Enzyme replacement therapy
Erythrocyte carriers have been employed for the delivery of therapeutic enzymes that require prolonged systemic activity or are otherwise prone to rapid inactivation. For example, glutamine synthetase, adenosine deaminase, and β-galactosidase have been successfully encapsulated within erythrocytes to treat metabolic conditions such as hepatic encephalopathy and enzyme deficiencies. In these cases, erythrocytes serve as circulating bioreactors that allow continuous enzymatic conversion of target substrates while protecting the enzymes from immune clearance.
Anticoagulation and thrombolysis
EBDDS carriers have been used to deliver anticoagulants such as low molecular weight heparin (LMWH) and thrombolytic agents like plasminogen activators (PAs). Encapsulation helps maintain therapeutic levels in circulation and prevents rapid renal clearance. Importantly, this strategy allows antithrombotic activity to be confined within the vasculature, thereby minimizing hemorrhagic risks associated with systemic administration. [11]
Immunomodulation
Erythrocyte-based carriers have enabled targeted delivery of immunomodulatory agents with reduced immunogenicity. Peptide antigens covalently linked to erythrocyte membranes have been used to induce antigen-specific immune tolerance in preclinical models of autoimmune diseases such as multiple sclerosis and type 1 diabetes. This strategy suppresses auto-reactive T and B cell responses without broadly suppressing the immune system. In oncology, erythrocyte-encapsulated interleukin-2 and tumor-associated antigens have been used to stimulate anti-tumor immune responses and enhance vaccine efficacy. [11]
Macrophage-directed therapies
Due to their natural clearance by the reticuloendothelial system, erythrocyte derived nano-vesicles have been leveraged for targeted drug delivery to macrophages. These carriers are especially suited for administering hydrophilic drugs like clodronate, a bisphosphonate used to deplete macrophages. Studies have shown that erythrocyte-derived nano-vesicles preferentially accumulate in macrophage-rich organs such as the liver and spleen, and can achieve more efficient cellular uptake and reduced toxicity compared to traditional liposomal formulations.
Challenges and future prospects
While EBDDs offer a lot of advantages - biocompatibility, prolonged circulation, and immune evasion - they are not without their limitations. [1] These systems are able to utilize the natural properties of red blood cells to improve the therapeutic delivery, but translating them from the lab to clinical use involves overcoming biological, technical and regulatory barriers.
Challenges
EBBDSs face several biological and practical challenges. Techniques like microfluidics, electroporation, and dialysis, though effective for loading the drugs, can compromise the integrity of the membrane and reduce the viability of erythrocytes. Achieving high loading efficiency without damaging the erythrocytes remains a important challenge, especially for commercial or large-scale applications. Controlled drug release strategies are still in development, and current methods like pH-sensitive or passive systems often lack the precision that is required for consistent outcomes. Surface modifications or drug attachments can also increase recognition by the immune system, which reduces the circulation time and overall effectiveness. In addition to these technical obstacles, logistical and regulatory issues complicate clinical translation. These challenges include maintaining sterility, sourcing erythrocytes, and standardizing preparation protocols across batches. [1]
Future prospects
Despite these challenges, future research efforts are focused on addressing the current challenges and exploring clinical applications of EBDDSs. Innovations in synthetic biology and nanotechnology are enabling hybrid erythrocyte-based platforms with enhanced controlled drug release and targeting. These systems can be engineered to respond to stimuli such as enzymatic activity or pH, which improves the site-specific delivery. Erythrocyte-derived carries also show the potential for personalized medicine and gene therapy, particularly for delivering RNA-based therapies and CRISPS components. [11] Additionally, integrating the diagnostic agents into these systems supports real time monitoring and theranostic applications. While further research is needed to overcome the technical and regulatory obstacles, interdisciplinary advancements continue to move EBDDSs close to a clinical reality.
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