Theranostic Applications of Nanodecoy for Diseases

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1		Koyeli Girigoswami	--	5153	2023-01-10 04:01:10	\|
2	We have inserted the references at the end of the manuscript.	Koyeli Girigoswami	Meta information modification	5153	2023-01-10 04:07:27	\| \|
3	format change	Peter Tang	Meta information modification	5153	2023-01-10 04:54:02	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15010073

Nanoparticles (NPs) designed for various theranostic purposes have hugely impacted scientific research in the field of biomedicine, bringing forth hopes of a future revolutionized area called nanomedicine. A budding advancement in this area is the conjugation of various cell membranes onto nanoparticles to develop biomimetic cells called ‘Nanodecoys’ (NDs), which can imitate the functioning of natural cells. This technology of coating cell membranes on NPs has enhanced the working capabilities of nano-based techniques by initiating effective navigation within the bodily system. Due to the presence of multiple functional moieties, nanoparticles coated with cell membranes hold the ability to interact with complex biological microenvironments inside the body with ease.

nanodecoys biomimetic cells ghost cells cell membrane coating nanotheranostics

1. Introduction

For the last couple of decades, nanoparticles ranging in size between 1 to 1000 nm have been intensively studied and worked on in drug delivery mechanisms. Nanoparticles have shown immense potential in the field of biomedical sciences due to their vivid physiochemical properties, easily manipulable properties, and structures ^[1]. The advantages of nanoparticles are their high loading capacity, tunable physiochemical properties, solubility, stability, in vivo behavior, ability of specific targeting, and increased efficacy. Nanoparticles have an extended circulation life, and they remain in the system for a longer time than directly administered drugs ^[2]. By nanosizing a formulation, the dissolution rate of the drug can be increased, leading to the enhancement of the absorption levels of the drug and its bioavailability. Improved tissue selectivity was achieved by using nanoparticles and they can be used to enhance protection. They are also used in renal clearance of drugs that are readily degraded or have short half-lives, such as small peptides and nucleic acids, for pharmacological effects ^[3].

In most scenarios, directly administered drugs have a very short lifespan. Due to the uneven distribution of the drug component in the blood, they are very difficult to exterminate from the body system. The non-uniform distribution also leads to low targeting efficiency levels. Improper distribution of the drug may also cause unwanted adverse reactions in other cells of the body by tampering with their normal functioning. To counter these shortcomings, nano-drug delivery systems have been developed. Nanoparticles work as brilliant carriers of drugs, genes, or vaccines. They are extremely biocompatible and work well in a suitable biosystem. All the properties of the outcomes also majorly depend on the method chosen for the preparation (Figure 1). Due to their high specificity and targeting efficiency, comparatively lower amounts of the drug are incorporated into the living system, thus reducing the toxicity level ^[4].

Figure 1. Method of fabrication of nanodecoys.

2. Toxicological Aspects of Nano-Based Drug Delivery System

Just like a coin has two sides, even nanoparticles have their equal share of advantages and disadvantages. The usage of nanoparticles has eased the drug delivery system considerably by adding desirable features such as long circulation life, specific targeting system, and toxicity reduction. However, nanoparticles have certain limitations, which curtail their clinical abilities. Most nanoparticles are unable to overpower the body’s immune response. Surface functionalization, such as PEGylation of nanoparticles, is performed to reduce the susceptibility in elimination via the reticuloendothelial system (RES). Various studies have identified that repetitive use of PEGylated nanoparticles induces an immune response in the body, leading to faster elimination of nanoparticles and curbing their translation. The favored targeting capacity of nanoparticles depends on the modification of the surface, which is challenging to fabricate and formulate ^[5].

The existing delivery system contributes significantly to in vivo applications. However, nanosystems still suffer barriers in the delivery system due to obstructions placed by the immune system, biological adhesion, and specific site targeting. The PEGylation or addition of phospholipid modifiers has been shown to be helpful in extending the time of circulation due to their high hydrophilicity. These simple modifications can readily inhibit the bio-adhesion of blood constituents and also inhibits RES uptake. Despite the successful implementation of surface modifications, synthetic nano-based systems tend to induce an adverse immune response and accelerate rapid clearance. Therefore, it is necessary to develop a bio-surfacing approach to improve current synthetic nanosystems, which enables prolonged circulation time to provide an efficient therapeutic effect ^[6].

3. Cell Membrane-Coated Nanocarrier System

Cells communicate with the environment they thrive in and other neighboring cells via a very integral structure called a cell membrane. Cell membranes, the outermost layer of a cell, is made up of a dual layer of lipoproteins. This lipoproteinaceous layer functions in keeping the contents of the cell separated from the surrounding matter. Its exterior part is hydrophilic, and the interior parts are hydrophobic in nature. The cell membrane ensures the interaction between the cell cytoplasm and the surrounding environment. Cells require a selective range of nutrients for their proper functioning. They also require a set amount of water and the elimination of toxic materials from it. This happens efficiently due to the semi-permeability of the membrane. They can carry out selective intake and excretion of different materials. Cell membranes also provide a platform for cell recognition markers that are genetically unique. These markers can guide the cell to identify the difference between a foreign material and known material. This property aids the immune system of the cell/organism to build a defense system and helps to maintain the cellular environment. The cell membrane has the ability to form encapsulated vesicles, which work as physical barriers between the core and surroundings of the vesicles. These may be used to design carriers for the delivery of drugs and also act as a template for the synthesis of nanoparticles. Source cells can be processed to isolate the cell membrane with functional groups on the surface and empty the interior contents by making a hollow vesicle. These types of hollow cells without a nucleus are named Ghost cells. Desired molecules can pass through the cell membrane while unwanted molecules cannot, which can serve as a nanoreactor to permit substrates to travel in and out of the cell membrane. They also prevent the interior vesicular enzymes from denaturation ^[7].

Another integral function of the cell membrane is cellular communication during various biological processes, which occurs by transmitting and receiving information. Cells contain unique surface molecules like receptors that act as signatures, which enable cellular recognition, migration, activation, and several other such functions. Red blood cells, for instance, have a circulation period of approximately 120 days. Biomolecules interact with specific cells by binding to the receptors found on the membrane through the ligand–receptor binding mechanism (lock and key mechanism). Thus, it can be inferred that these biomolecules can in turn communicate with cell membrane-coated nanoparticles (CM-NP) by binding to the same specific receptors ^[6].

One of the major targets that researchers aim to achieve in this field of nanomedicine is the effective and efficient targeting of a drug at a specific site and proper binding in vivo. A longer circulation period is the most necessary feature that is considered while developing a nanomedicine to ensure appropriate targeting (active or passive delivery). Surface modification is the most advantageous conception of a range of nanoparticles, which enhances their circulating performance in vivo. The cell membrane-coating strategy enables the nanoparticle-based drug delivery system to circulate in the bloodstream without any hindrances. Compared to artificially synthesized vesicles composed of lipid bilayers, naturally derived cell membrane-based vesicles consist of several membrane-related surface functional groups, such as proteins, carbohydrates, and antigens. This function protects the cell, prevents biofouling, and instigates specific recognition and intracellular communications. Recently, several natural cells such as erythrocytes, thrombocytes, stem cells, cancer cells, macrophages, and bacterial cells (E. coli) (Table 1) served as the vital source for the extraction of the cell membrane and constructed versatile functioning bio-hybrid delivery systems through the bottom-up approach (self-assembly) ^[6]^[8].

Table 1. Recent Advances in Nanodecoys for Biomedical Applications.

S. No	Cell Membrane/Extraction and Coating Method	Nanoparticles	Surface Modifications	Drugs	Target Cell/Disease/Pathogen	Applications/Functions and Limitations	Key Features	References
1.	Macrophage. The extrusion technique was used to coat macrophage membranes on gold–silver nanocages in order to fabricate macrophage-membrane-coated nanoparticles.	Gold/Silver nanocages	-	Rhodamine B	Osteomyelitis and local infection	Anti-bacterial photothermal therapy. Using macrophage membranes coated with bacterial pretreatment, this nanosystem can be used for precision/personalized medicine. The unique construction of gold-silver nanocages (hollow interiors and porous walls) makes it possible to load antibacterial drugs within these nanosystems for on-demand controlled release under NIR light. Limitations exist for the clearance of metal nanoparticles from our bodies.	Improved the bactericidal effect upon irradiation of NIR	^[9]
2.	Erythrocytes. In order to prepare human RBC nanosponges (hNS), three steps were taken: (i) hypotonic treatment of packed hRBCs to obtain RBC membranes, (ii) nanoprecipitation by adding poly(lactic-co-glycolic) acid (PLGA) in organic solvents to an aqueous phase to prepare polymeric cores, and (iii) sonication of hRBC vesicles onto PLGA cores.	Polymeric nanoparticles	-	-	Hemolytic toxins	Neutralizing the effectiveness of pore-forming toxins (PFTs). hNS was tested against four representative PFTs (melittin, listeriolysin O, α-hemolysin, and streptolysin O) in vitro and in vivo for its capacity to absorb and neutralize these toxins. Limitations of this study involve the risk of blood-borne diseases if the isolation process of the erythrocyte is compromised. Scaling up human erythrocyte-derived membranes has ethical issues.	The nanosponges possessed novel antivirulence applications against hemolytic toxins of various strains of bacteria	^[10]
3.	Neutrophil. For the synthesis of neutrophil-NPs, purified and activated human peripheral blood neutrophil plasma membrane was coated onto poly(lactic-co-glycolic acid) (PLGA) polymeric cores.	PLGA	-	-	Rheumatoid arthritis	Anti-inflammatory strategy. Their prophylactic regimen was used to test the effectiveness of neutrophil nanoparticles in treating early-stage arthritis in CIA mice. The limitation of this study is the scaling up of neutrophil-derived membranes and manufacturing issues.	The particle neutralized the proinflammatory cytokines, targeted the cartilage matrix, and suppressed the severity of arthritis	^[11]
4.	Platelet. A repeated freeze-thaw process was used to extract platelet membrane from platelet rich plasma (PRP). Nanoprecipitation was used to prepare the PLGA cores. PLGA nanoparticles (PNP) were prepared by mixing the nanoparticles with PEGylated platelet membrane and sonicating them. PNP loaded with rapamycin (RAP-PNP) was prepared using the same method except that 800 mg of rapamycin was added to the PLGA solution.	PLGA	-	Rapamycin	Atherosclerosis	Targeted drug delivery. By mimicking platelets’ inherent adhesion to atherosclerosis plaques, poly(DL-lactide-co-glycolide) nanoparticles (PNP) were explored as a drug delivery system targeting atherosclerosis plaques using the immunosuppressant Rapamycin (RAP). In apolipoprotein E-deficient (ApoE-/-) mice, PNP encapsulating RAP (RAP-PNP) was tested for anti-atherosclerosis activity against atherosclerotic plaques both in vitro and in vivo. The limitation of this study was that the membrane is human-derived, which can have ethical concerns. Moreover, it induces macrophage autophagy, which may interfere with normal homeostasis.	Target and delay atherosclerotic plaques. A promising platform for the treatment of atherosclerosis	^[12]
5.	Cancer cell. Adenocarcinoma cells (MCF-7) were sonicated in buffer solution with protease inhibitor cocktail and differentially centrifuged to isolate the membrane. In order to form yolk-shell-structured nanoparticles, they first coated liposomes with a lipid bilayer coating (LM), then wrapped them with MCF-7 cell membrane (CCM) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), respectively, to form CCM@LM and L@LM, respectively, using mesoporous silica nanoparticles (MSN).	Mesoporous silica nanoparticle	PEGylated liposome	Doxorubicin and mefuparib hydrochloride	Cancer chemotherapy	Targeted drug delivery. NPs coated with CCM and with a yolk-shell structure were evaluated for cancer chemotherapy. In addition to its homologous tumor-targeting ability due to the CCM coating, the resulting formulation (CCM@LM) exhibited a favorable immune escape profile. The limitation of this study is that we have to be careful while isolating the membrane from cancer cells regarding any residual cells’ presence.	Significantly improved the antitumor effect compared to chemotherapeutic drugs (Doxil)	^[13]
6.	Erythrocytes. RBC membrane RBCM was formed by breaking up RBCs extracted from nude mice, and then incubating them under low osmotic pressure. As RBCM is sonicated, its size degrades from micro to nano. Perfluorocarbon (PFC) nanoparticles were encapsulated within biocompatible poly(d,l-lactide-co-glycolide), PLGA, resulting in PFC@PLGA nanoparticles, which were then coated with RBCM.	Perfluorocarbon nanoparticles	PLGA	-	Cancer radiotherapy	Therapy. By diffusing oxygen through blood vessels, PFC@PLGARBCM with nanoscale sizes could improve the overall oxygenation status of the tumor after i.v. injection and the tumor is relieved from hypoxia, which can enhance the tumor inhibition by radiotherapy (RT). The limitations exist regarding the oxygen supply to the interior part of the tumors, which may inhibit the necrosis of the tumor.	Delivery of oxygen and favorable for cancer treatment	^[14]
7.	Platelet. A freeze-thaw process was used to extract platelet membranes. A model drug for rheumatoid arthritis (RA), FK506-loaded nanoparticle cores were prepared by the process of nanoprecipitation. Platelet-mimetic nanoparticles (PNPs) were prepared by mixing PLGA nanoparticles with platelet membrane solutions and sonicating them to fuse the membrane onto the cores of the nanoparticle.	PLGA nanoparticles	-	Model drug- FK506	Rheumatoid arthritis	Targeted drug delivery. CIA mouse model of RA showed significant RA progression control with FK506-PNPs, and preliminary safety studies showed excellent biocompatibility for PNPs. Limitations include the scaling up of the ghost cells, i.e., the platelet membrane requires human platelets, which has ethical concerns.	Accurate accumulation of formulation in the inflammatory synovial tissue.	^[15]
8.	Cancer cell. PLGA nanoparticles, containing siRNA and dox was prepared by water in oil emulsion method. Hela human cervix carcinoma cells and MDA-MB-231 human breast cancer cells were suspended in typical hypotonic lysing buffer and lysed in ice bath with repeated freezing and thawing. The membranes were collected using repeated centrifugation. In order to obtain membrane vesicles, the above cancer cell membrane fragments were extruded for 20 passes through a 400 nm polycarbonate membrane. To coat the membrane vesicles onto PLGA cores, nanocores and membrane vesicles were co-extruded through a 200 nm polycarbonate membrane.	PLGA nanoparticles	-	Doxorubicin and PD-L1 siRNA	Cancer therapy	Targeted drug delivery. PLGA nanocores loaded with doxorubicin (Dox) and siRNA targeting PD-L1 (si.PD-L1) were constructed, camouflaged, and functionally modified using a cancer cell membrane (CCM). In addition for targeting homologous source cells, CCMNPs also have great potential as a platform for guiding the delivery of homologous-targeting therapeutics. PLGA nanoparticles cloaked in Hela membranes exhibited more powerful cellular internalization when compared with bare PLGA nanoparticles, while MDA-MB-231 cells showed reduced nanoparticle binding. Cell membrane isolation from cancer cells may also contain some unlysed cells which may contaminate the product, making this a limitation of this study. Moreover, the extracellular matrix of cancer cells may impart deleterious effects on normal cells which needs to be addressed.	Selective accumulation and sustained delivery of drugs	^[16]
9.	Macrophage. Solvothermal method was used to synthesize Fe₃ O₄ NPs. Membrane-derived vesicles (MM-vesicles) were prepared using RAW 264.7 cells that were suspended in hypotonic lysing buffer containing EDTA-free mini protease inhibitor tablet. The cells were then subjected to Dounce homogenizer for disruption. After isolating the membranes using centrifugation, the MM-vesicles were extracted by physical extrusion of the pellets. The pellets were passed several times through 400 nm and 200 nm microporous membranes using an Avanti mini extruder. Fe₃O₄ NPs synthesized earlier were mixed with MM-vesicles and extruded through a 200 nm membrane 11 times and the additional MM-vesicles were removed using an external magnetic field; the resultant Fe₃O₄@MM NPs solution was left in PBS.	Magnetic iron oxide	-	-	Breast cancer therapy	Photothermal therapy. MM-vesicles (macrophage membrane-derived vesicles) were collected from macrophages and then coated on Fe₃O₄ NPs. A macrophage membrane camouflaged nanoparticle (Fe₃O₄@MM NPs) inherited good biocompatibility and immune evasion properties and was capable of targeting cancer and converting light to heat. It could be used for enhanced photothermal tumor therapy. The fascinating properties of macrophage membrane coatings in evading immune cells and targeting cancer require further investigation. Limitations include the scaling up of membranes from macrophages.	Exhibited great biocompatibility and light-to-heat conversion capabilities	^[17]
10.	Erythrocytes. The Prussian blue nanoparticles (PB NPs) were prepared using the precipitation method using citric acid as a capping agent. The whole blood was collected from the eyeball of female KM mice and centrifuged for plasma removal. The RBCs were hemolyzed using distilled water and the membrane was selected using centrifugation. The vesicles were collected by sonication of the membrane followed by a series of extrusions using 400 nm and 200 nm polycarbonate membranes. Ce6 solution was added to these vesicles for binding and excess Ce6 was removed by centrifugation. To prepare PB@RBC/Ce6 NPs, PB NPs were added to RBC/Ce6 vesicles prepared previously and extruded using 100 nm membrane several times to yield the final product, PB@RBC/Ce6 NPs.	Prussian blue nanoparticles		Chlorin e6	Dual cancer therapy	Photothermal and photodynamic therapies. Prussian blue nanoparticles (PB NPs) coated with photosensitizing agent Chlorin e6 (Ce6)-embedded RBC membrane vesicles, named PB@RBC/Ce6 NPs, were synthesized. A nude mouse orthotopic tumor model was used to assess the cytotoxicity and therapeutic efficacy of PB@RBC/Ce6 NPs in vivo and in vitro assay was done using 4T1 cell line. The findings of the study suggested that erythrocyte membranes are efficient carriers of the photosensitizer Ce6 due to hydrophobic interaction. They could impart efficient PTT with higher biocompatibility and higher endocytosis in tumor sites imparted synergistic PDT and PTT-mediated cell killing to inhibit cancerous tumor growth. Limitations of this study may be the ethical considerations in the scaling up of the erythrocyte membranes.	Produced a notable effect in boosting the necrosis and showed a synergistic therapeutic effect	^[18]

4. Applications

The bio-mimicking ability of the nanodecoys allows them to function inside the biological system with negligible adverse effects. Thus, they are considered the best candidate for therapeutic applications, namely, drug delivery, detoxification, vaccination, immunomodulation, photodynamic therapy, etc. (Figure 2). Owing to their multifunctional properties, they are also being used to carry diagnostic agents for bioimaging applications. Integration of diagnosis and therapeutic characteristics of nanodecoys lead to theranostic applications where a single particle could perform both activities simultaneously.

Figure 2. Biomedical applications of nanodecoys.

4.1. Bioimaging

Anomalies of the internal structures, the presence of foreign bodies, and the state of disease condition have been examined to design appropriate therapeutic procedures. As for cancer, there are two components of detection: (i) Screening and (ii) Downstaging, i.e., early diagnosis. Screening refers to testing a healthy individual for the presence of a tumor even before the symptoms, whereas early detection is testing over the appearance of minor symptoms. Early detection of cancer provides a high curable rate with long-term management. For improved information on anatomical and functional activities of the disease condition, nanostructures are being employed, mostly in oncology. Due to the ease of tuning the physical and optical properties, nanoparticles are excellent candidates in the imaging field. Surface functionalized nanoparticles can indisputably distinguish between healthy tissues and abnormal lesions. Present contrast agents (CA) exhibit fast metabolism, and tumor tissue detection is limited due to the spatial resolution that is generated by the hardware of imaging modalities. The distribution is usually non-specific, which in turn affects the resolution of images. Therefore, the CA can be effectively transported to the tumor site through nanocarriers. There are four ways where nanoparticles can help in the imaging field: (i) NPs as CA: optical properties of the nanoparticles such as upconversion nanoparticles (UCNPs) aids in imaging applications, (ii) NPs as a carrier of CA: to deliver CA with other imaging elements, nanoscaled carrier systems are being used, (iii) NPs to detect biomarkers: detection of biomarkers in certain cancer types are very arduous, while studies found that nano-based biosensors can significantly amplify the signal from tumor area, (iv) NPs to spot circulating tumor cells (CTCs): NPs are found to be a standalone material as a CTC capture device. Rao et al. demonstrated that erythrocyte membrane-coated UCNPs surface functionalized with folic acid receptors for specific binding. The in vivo study showed enhanced tumor imaging with negligible systemic toxicity ^[19]. For highly specific tumor imaging, the same group synthesized UCNPs coated with a cancer cell membrane that was sized about 80 nm. The surface of the particle was further modified with PEGylated phospholipids, which were sized about 10 nm. Both the cancer cell membrane and UCNPS showed fluorescence emission. The same formulation coated with erythrocyte was employed as control. The in vivo investigation was carried out in a mouse model. The overall results suggested that the CCNDs can be remarkably used in highly specific tumor imaging. To test the virulence factor of the membrane derived from the cancer cell, it was injected into an immunodeficient mouse and showed no tumor development ^[20]. Zhang et al. employed cancer cell membranes to encapsulate rare-earth doped nanoparticles (REDNPs). For comparison, REDNPs were encapsulated with PEG and a similar treatment was provided. Compared to the PEGylated particle, CCNDs showed enhanced imaging of tumor cells in NIR-II window with decreased relative uptake by the spleen and liver ^[21].

4.2. Drug Delivery

Site-specific delivery can be achieved by nanoscaled materials. Transportation of drugs specifically to the diseased site could significantly minimize the toxic effects. Recently, the naturally derived membrane coating of nanoparticles has gained more attention since it enhances the properties of a particle. There are three major highlights of membrane coating: (i) due to the presence of surface protein on cell membranes, coating them with nanoparticles can improve the targeting and attain selective accumulation on diseased sites, especially in the tumor microenvironment, (ii) due to the biomimetic membrane characteristics, it can readily escape the biological barriers and immune responses, (iii) the circulation time of the particle in the bloodstream can be prolonged. Overall, nanodecoys have emerged as a promising class of theranostic agents in managing and treating a plethora of diseases ^[7]. The research team of Chen recently utilized an erythrocyte membrane to formulate a nano-based drug carrier vehicle for delivering paclitaxel. A lipid insertion method was used to prepare the vehicle tagged with bispecific recombinant protein for specific tumor targeting. The formulation was tested for stability and showed in vitro stability for 8 days. The prepared particle was sized about 171 nm and was spheroid in shape. The release profile was studied, which showed a biphasic pattern. The in vivo results conducted on the gastric cancer-bearing mouse model demonstrated a specific accumulation of drugs on the target site and eliminated about 61% of tumor volume ^[22]. Li et al. fabricated a drug delivery vehicle by coating macrophage-derived microvesicles onto PLGA nanoparticles loaded with tacrolimus as a model drug. The particle was tested on an in vivo mouse model induced with rheumatoid arthritis. The team used a novel method to prepare the macrophage by implying cytochalasin B and analyzed it through iTRAQ technology (isobaric tags for relative and absolute quantitation). The particle was further tagged with two different dyes: DiR and DiD to obtain multicolor imaging. For the comparison, bare nanoparticle and erythrocyte-coated nanodecoys were used. After the intravenous administration of three sets of samples and control to the mouse, the evaluation showed increased efficiency in macrophage-coated NPs ^[23]. Thrombocytes, being the smallest blood cells, exhibit superior functionalities as they can escape phagocytosis by macrophages. Hence, it is believed that TNDs can prolong circulation in vivo. Wang et al. developed a drug carrier by encapsulating PLGA nanoparticles in a platelet membrane shell to deliver bufalin. The in vivo and in vitro studies revealed that the prepared particle showed a sustained drug release profile and targeted release of the drug. The toxicity of the formulation was evaluated in a cancer-induced mouse model to analyze the biosafety and tumor inhibition rate. The overall results demonstrated that the TNDs performed site-specific drug delivery with minimal adverse effects ^[24].

4.3. Photodynamic Therapy (PDT)

Studies have demonstrated that PDT is an effective, clinically approved therapeutic procedure for treating cancer and pre-cancer due to its minimum invasiveness and minimal cytotoxic activity. The principle of PDT depends on the generation of ROS by the photosensitizer that destroys cells ^[25]. After administration of the dye, the site that needs to be treated alone can be irradiated to avoid killing healthy cells. Since this occurs only when it is irradiated, it holds several advantages. Encapsulation of photosensitizer in a nanoparticle can reach the site precisely and perform selective accumulation on tumor cells, which minimizes the distribution level and increases the bioavailability of the given photosensitizer. Still, PDT is not being chosen as the first-line treatment of cancer due to certain shortcomings, and it is one of the most preferred procedures during a situation where the condition does not allow surgical removal. Knowledge about the fate of nanoparticles after performing the programmed functions is still lacking; furthermore, the cytotoxic profile of nanoparticles needs a forum to discuss in detail before employing them in real-time applications such as PDT to prevent other infections. Unlike radiation-mediated treatment procedures, PDT can be repeated several times and offer long-term cancer management where a complete cure is impossible. To overcome the limitations that nano-mediated PDT currently faces, cell membrane-coated nanoparticles, so-called nanodecoys, can be employed. The biocompatibility of nanoparticles can be enormously enhanced by coating them with nanodecoys. For the core to encapsulate photosensitizers, mesoporous silica nanoparticles (MSN) are being widely used due to their porous structure and easy surface modification. Wang et al. recently worked with HCNDs, which were prepared with MSN as a core to encapsulate hypoxic prodrug, tirapazamine, and a photosensitizer, indocyanine green, coated with erythrocyte membrane and cancer cell membrane. Since the hypoxic condition of the tumor microenvironment is one of the limitations of PDT, the team co-loaded the hypoxic prodrug along with photosensitizer. The in vivo experimental results performed on a tumor-bearing mice model showed tumor inhibition rates of 34% and 64% for the MSN encapsulated co-drug loaded nanoformulation and membrane-encapsulated nanoformulation, respectively ^[26]. Peng et al. extracted OMVs from E.coli bacterium. The nanoscaled membrane was further modified with indocyanine green and targeting ligand. Upon irradiation to near-infrared light, the particle synthesized featured photodynamic activities along with photothermal and apoptosis induction by TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). This showed enhanced therapeutic performance and complete eradication of skin melanoma ^[27]. Zhao et al. constructed a metal–organic framework (MOF) (FeTCPP/Fe₂O₃) by incorporating ferric oxide and a porphyrin-based photosensitizer via the liquid diffusion method. In order to enhance biocompatibility and circulation time, the formulation was coated with an erythrocyte membrane and tagged with synthetic DNA aptamer (AS1411). After excellent results were obtained from the in vitro study conducted with human epithelial carcinoma cells, the study was further carried out on an in vivo mouse model. The MOF nanomaterial showed improved PDT effects in ENDs ^[28].

4.4. Theranostics

Integration of the diagnostic and therapeutic abilities of a single particle will enable it to perform both functions simultaneously. These multifunctional nanoparticles possess several advantages, including enhanced imaging of tumor sites, site-specific drug delivery, enhanced EPR (enhanced permeation and retention effect), and monitoring ^[29]^[30]^[31]^[32]^[33]^[34]. Thus, theranostic particles are highly beneficial for planning personalized medicine. Encapsulation of theranostic particles onto cell membranes can further improve biocompatibility by eliminating possible interactions with the immune system. There are four general ways to fabricate a theranostic particle: (i) therapeutic agent can be encapsulated or conjugated onto imaging NPs such as SPION, UCNPs, quantum dots, etc. ^[35]^[36]^[37], (ii) CA can be tagged onto a therapeutic nanoparticle such as silver nanoparticles, etc. ^[38], (iii) both the CA and therapeutic agent can be encapsulated onto a biocompatible NPs such as polymeric NPs, nano-vesicles, MSN, etc., (iv) engineering of unique NPs with imaging and therapeutic potential is possible with PEGylation to improve biocompatibility. Despite continuous efforts, theranostic NPs are still in translational stages due to three major concerns: insufficient data on the systemic evaluation of biosafety of the particle, cytotoxicity, and obtaining expected clinical effects. Rao et al. extracted membranes from erythrocytes to encapsulate magnetic NPs via a microfluidic electroporation method with a size of about 60 nm in diameter. The properties of both the membrane coating and the core were blended to produce image-guided therapy. Magnetic NPs in the core exhibited excellent magnetic and photothermal properties. The membrane coating could improve the biocompatibility and circulation time of the particle in the bloodstream. Thus, the prepared nanostructure was used to perform the magnetic resonance imaging (MRI) assisted photothermal therapy when tested in vivo ^[39]. Recently, Li et al. reported dual model image-guided photodynamic therapy for tumor treatment. For the core material, SPION crosslinked with styrene and acrylic acid and sized about 9 nm was used. The surface of the particle was then coated with polyethyleneimine (PEI) through electrostatic interaction, and the chlorin e6 photosensitizer was tagged along with PEI. Two sets of particles were prepared for comparison: core-encapsulated photosensitizer and core-encapsulated photosensitizer-coated tumor cell membrane. Both sets were tested for the ability to generate ROS and the MR/NIR fluorescence imaging on an in vivo mouse model. The results demonstrated that CCNDs provided better efficiency than bare NPs ^[40]. Gene expression is one of the major causative conditions for cancer, and the overexpression of certain genes is noted in most of the tumors. Planning gene therapy along with conventional treatment techniques is considered one of the best beneficial treatment strategies. Mu and colleagues designed stem cell membrane-coated magnetic nanoparticles to deliver siRNA. The siRNA could effectively inhibit the expression of the polo-like kinase-1 (Plk-1) gene, which would further cause apoptosis. The synthesized particle provided image-guided combinational photothermal and gene therapy when tested on an in vivo mouse model bearing prostate cancer ^[41].

The advantages and applications of nanodecoys are depicted in Figure 3.

Figure 3. The advantages and theranostic applications of nanodecoys.

4.5. Other Applications

The above-mentioned applications are some of the renowned fields where nanodecoys are widely used. Other applications include immunomodulation, detoxification, enhancement of particle properties, and vaccination. The outer surface of nanodecoys consists of several sites for binding with complementary-shaped receptors or antibodies. Several researchers are currently involved in developing nanodecoys for immunomodulation ^[42]. The toxicity of the particle, i.e., the core properties, could be effectively controlled by a biocompatible coating of the cell membrane; thus, they could enhance the characteristics. Toxins are secreted by various organisms for their survival, which could bind to a nearby cell, deform the shape, and disrupt normal metabolic functions. Hence, nanodecoys during this stage could be employed to detoxify the toxin moieties. Polymeric nanomaterials and nanosponges are two widely used materials for detoxification applications. Recently, Gong et al. reported the synthesis of polymeric nanoparticles encapsulated in the mitochondrial cell membrane. The outer mitochondrial membrane (OMM) was capable of binding with B-cell lymphoma protein inhibitor molecule (ABT-263) and protected cells from ABT-263 mediated apoptosis ^[43]. Chen et al. demonstrated the neutralization behavior of erythrocyte membrane-coated polymeric nanosponges. The prepared formulation acted as a toxin decoy and effectively neutralized the broad spectrum of hemolytic toxins ^[10]. Cell membranes are also being produced, modifying the general features for them to perform better. Owing to this, Park et al. engineered a genetically modified cell membrane to encapsulate polymeric nanoparticles loaded with dexamethasone to treat inflamed lungs. The inflamed lungs overexpress VCAM-1 (vascular cell adhesion molecule-1. The cell is genetically modified to express VLA-4 (very late antigen-4), which can specifically target and bind to the VCAM-1 of inflamed lungs, thus providing targeted drug delivery. The results obtained from the work suggest that the cell membranes can be tailored in a desired way to perform particular functions ^[44]. Another important field of application of nanodecoys is vaccination. The development of vaccination to provide cancer immunotherapy is of great interest currently.

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Subjects: Materials Science, Biomaterials

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Sampreeti Chatterjee

Karthick Harini

Agnishwar Girigoswami

Moupriya Nag

Dibyajit Lahiri

Koyeli Girigoswami

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Update Date: 10 Jan 2023

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