Biosensors and Nanotheranostics

1. Introduction

Over the past several decades, nanomedicine has reorganized how drugs and diagnostic probes are delivered, trading free-drug pharmacokinetics for engineered nanoscale vehicles that can improve solubility, tune release, and blunt off-target toxicity (Chennamsetty et al., 2026; Li et al., 2026b). Conventional synthetic carriers—liposomes, polymeric micelles, dendrimers, and an expanding catalogue of inorganic nanomaterials—have carried this idea into the clinic across oncology and inflammatory disease (Guo et al., 2025; Muhammad et al., 2026). Yet the same platforms that behave so well in a cuvette tend to falter in the body, where a crowded, reactive biological environment erodes much of their designed advantage (Li et al., 2026b; Zhang et al., 2023).

The core difficulty is one of recognition. Within seconds of intravenous injection, a pristine synthetic particle is read as foreign: plasma proteins adsorb onto its surface and assemble a dynamic “protein corona” dominated by opsonins such as immunoglobulins and complement fragments, handing the particle a new biological identity it never asked for (Chennamsetty et al., 2026; Fadeel, 2022). That identity is a clearance signal. Tissue-resident phagocytes of the mononuclear phagocyte system (MPS)—chiefly Kupffer cells in the liver and macrophages in the spleen—sequester the particle before it reaches its target (Fadeel, 2022; Zhu et al., 2022). The classic engineering answer, grafting polyethylene glycol (PEG) to create a steric “stealth” layer, has proven only partially durable: repeated dosing provokes anti-PEG antibodies and the accelerated blood clearance (ABC) phenomenon, and PEGylation does nothing to help a particle cross a pathological barrier (Li et al., 2026b; Yun et al., 2026; Zhou et al., 2025). Active targeting through single synthetic ligand–receptor pairs face its own ceiling—receptor saturation, heterogeneous expression, and immunogenicity—leaving many nanotherapeutics stranded between preclinical promise and clinical reality (Chennamsetty et al., 2026; Zhu et al., 2022).

Biomimetic cell-membrane coating reframes the problem rather than attacking it piecemeal. Instead of synthesizing “self” signals one molecule at a time, this top-down approach cloaks a synthetic core in an intact plasma membrane harvested directly from a donor cell, transferring the cell’s surface identity wholesale onto the particle (Fang et al., 2018; Hu et al., 2011; Zhu et al., 2022). The resulting core–shell hybrid pairs the programmable stability, high loading capacity, and physicochemical flexibility of a synthetic core with the antigenic richness and biocompatibility of a natural membrane (Muhammad et al., 2026; Zhou et al., 2025).

What makes the strategy so flexible is that the membrane carries its donor’s functional repertoire with it. Erythrocyte membranes remain the benchmark for immune evasion: their dense display of cluster of differentiation 47 (CD47) engages signal regulatory protein alpha (SIRPα) on macrophages, delivering a “don’t-eat-me” signal that suppresses phagocytosis and stretches circulation into the range of dozens of hours (Oldenborg et al., 2000; Xia et al., 2019; Zhou et al., 2025). Leukocyte membranes exploit integrins and chemokine receptors to migrate toward inflamed tissue and, in some cases, to cross the blood–brain barrier (BBB) (Muhammad et al., 2026; Yun et al., 2026). Platelet membranes home to damaged endothelium and circulating tumor cells through P-selectin and glycoprotein complexes (Hu et al., 2015; Zhou et al., 2025), while cancer-cell membranes exploit homotypic adhesion for tumor-specific accumulation and antigen presentation (Chen et al., 2016; Sun et al., 2017). Fusing two or more membranes yields hybrids that combine these behaviors in a single shell (Dehaini et al., 2017; Jiang et al., 2019; Zhang et al., 2026).

Beyond targeted therapy, the same envelope has opened a path into theranostics. Encapsulating inorganic nanocores—superparamagnetic iron oxide, gold nanocages, copper sulfide, quantum dots—or radiolabeled chelates lets a single platform support magnetic resonance imaging (MRI), computed tomography (CT), near-infrared fluorescence (NIR-FL), photoacoustic (PA) imaging, and nuclear imaging (SPECT/PET), while the biological cloak shields fragile probes from premature clearance (Chen et al., 2016; Chetty et al., 2020; Liu et al., 2026; Zhu et al., 2022). Responsive cores then enable image-guided photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), and radioimmunotherapy with tight spatiotemporal control (Li et al., 2026b; Zhang et al., 2026; Zhu et al., 2022).

For all this preclinical momentum, translation stays constrained by technical, biological, and regulatory barriers (Chennamsetty et al., 2026; Li et al., 2026b; Shan et al., 2026). Manufacturing spans cell expansion, lysis, gradient purification, and membrane–core assembly, and each step introduces quality-control risk; donor heterogeneity drives batch-to-batch variability; incomplete removal of genomic DNA or oncogenic material raises biosafety concerns; and the correct right-side-out orientation of membrane proteins is difficult to guarantee at scale (Li et al., 2026b; Liu et al., 2021; Muhammad et al., 2026; Zhou et al., 2025). Layered onto storage instability and the regulatory ambiguity of “combination products,” these issues make standardized, good-manufacturing-practice (GMP)-compliant production the field’s central unsolved problem (Chennamsetty et al., 2026; Shan et al., 2026).

Although many reviews treat individual nanocarriers or specific applications of cell-membrane cloaking, few bring interfacial design, quantitative immune-evasion mechanisms, theranostic modalities, and translational barriers under one framework (Chennamsetty et al., 2026; Muhammad et al., 2026; Zhu et al., 2022). This review aims to:  Delineate the design principles and fabrication engineering of biomimetic nanoplatforms, comparing organic, inorganic, and hybrid cores and evaluating extrusion, sonication, and microfluidic electroporation for coating efficiency, structural integrity, and protein fidelity (Muhammad et al., 2026; Zhou et al., 2025; Zhu et al., 2022); Elucidate the molecular and immunological mechanisms of immune evasion, including the CD47–SIRPα axis, complement regulation, and selectin/integrin pathways, and their role in reshaping the protein corona (Fadeel, 2022; Muhammad et al., 2026; Yun et al., 2026);  Examine membrane-donor selection—erythrocytes, platelets, leukocytes, stem cells, cancer cells, bacterial vesicles, and hybrids—and how each cloak dictates disease-homing specificity (Muhammad et al., 2026; Yun et al., 2026; Zhou et al., 2025); Appraise the integration of precision delivery and multimodal theranostics across MRI, CT, optical, photoacoustic, and nuclear imaging coupled to synergistic therapy (Chennamsetty et al., 2026; Zhang et al., 2026; Zhu et al., 2022); Dissect translational bottlenecks—GMP-compliant production, CQA standardization, batch heterogeneity, membrane purity, immunological safety, and shelf life (Chennamsetty et al., 2026; Li et al., 2026b; Shan et al., 2026); and Offer a forward-looking roadmap built on biointerface engineering, genetic membrane modification, AI-guided formulation, and continuous-flow biomanufacturing (Li et al., 2026b; Muhammad et al., 2026; Yun et al., 2026).

2. Cell Membrane-Coated Biomimetic Nanoparticles for Immune Evasion, Targeted Delivery and Theranostic Applications in Disease

2.1 Conceptual framework and biointerfacial engineering

Modern pharmacotherapy has been pulled steadily toward targeted, nanoscale delivery—systems able to carry a potent payload or an imaging probe to diseased tissue while sparing healthy organs (Chennamsetty et al., 2026; Li et al., 2026b). Decades of synthetic chemistry have supplied a broad palette for this purpose, from organic carriers such as polymeric nanoparticles, liposomes, micelles, and nanosponges to inorganic platforms including gold nanoparticles, mesoporous silica, quantum dots, and superparamagnetic iron oxide (Guo et al., 2025; Liu et al., 2026; Yasin et al., 2025). These materials offer tunable size, high payload capacity, and controllable release, but their clinical translation is repeatedly undermined by the same biological clearance cascades described above (Li et al., 2026b; Zhang et al., 2023). Against that backdrop, cell-membrane coating is best understood not as another material but as a way of borrowing an interface the body already trusts (Fang et al., 2018; Hu et al., 2011; Zhou et al., 2025).

The overall logic of the approach—from donor cell, through membrane isolation and synthetic-core fabrication, to the assembled core–shell particle and its inherited functions—is summarized in Figure 1. The remainder of this section unpacks each element: the synthetic cores that define cargo and signal (Table 1), the fusion technologies that assemble the shell (Table 3), the donor membranes that program biological fate (Table 2, Figure 3), the immune-evasion machinery that keeps the particle in circulation (Figure 2), and the theranostic modalities these particles enable.

2.2 Synthetic core composition and functional specialization

The inner core is the cargo reservoir and physical scaffold; it sets encapsulation efficiency, stability, degradation behavior, and stimuli-responsiveness (Chennamsetty et al., 2026; Muhammad et al., 2026). Biodegradable polymers dominate the organic category. Poly(lactic-co-glycolic acid) (PLGA), polydopamine (PDA), and cyclodextrin-based nanosponges are widely used to deliver hydrophobic and hydrophilic drugs, chemotherapeutics such as doxorubicin and paclitaxel, and nucleic acids, with release governed by ester hydrolysis and matrix diffusion over days to weeks (Garg et al., 2024; Hu et al., 2011; Jan et al., 2023). PDA and metal–organic frameworks add photothermal conversion and pH-responsive dissociation (Liu et al., 2026).

Inorganic cores contribute intrinsic theranostic function (Zhu et al., 2022). Superparamagnetic iron oxide nanoparticles (SPIONs) and doped ferrites provide transverse relaxivity for MRI and allow magnetic-field-guided accumulation (Lin et al., 2020; Su et al., 2026). Plasmonic gold nanostructures and transition-metal chalcogenides—copper sulfide, bismuth selenide, molybdenum disulfide—absorb strongly in the near-infrared windows and serve as PA and PTT agents (Chen et al., 2016; Deng et al., 2022; Huang et al., 2025). More

Table 1. Synthetic and inorganic nanoparticle cores: physicochemical properties, cargo encapsulation, and theranostic modalities in biomimetic delivery systems. This matrix compares the principal core materials used beneath biomimetic membrane coatings, spanning biodegradable polymers, mesoporous and plasmonic inorganic scaffolds, coordination metallacycles, and liquid-crystalline cubosomes. For each platform it summarizes material classification and architecture, representative encapsulated drugs and imaging probes, the stimuli that trigger release (pH, glutathione, near-infrared light, or magnetic field), and the diagnostic or therapeutic modality conferred. The final column lists key biological findings and disease targets reported for each core, illustrating how the inner scaffold sets payload capacity, degradation kinetics, and intrinsic contrast while the membrane shell governs biological fate.

Table 2. Biological membrane donors, biointerfacial molecular signatures, and mechanistic disease-targeting tropisms. This table maps the major cellular sources used to camouflage synthetic cores onto the surface markers they contribute and the disease tropism those markers program. For each donor it records the key surface proteins and glycocalyx components, the molecular signaling or adhesion mechanism that drives targeting, the immune-evasion attributes transferred to the particle, and representative preclinical applications. Donors range from non-nucleated erythrocytes and platelets through myeloid leukocytes, cancer cells, bacterial outer-membrane vesicles, and mesenchymal stem cells, to engineered multi-membrane hybrids. The comparison shows how cellular origin, rather than core chemistry, dictates stealth, circulation longevity, and homing specificity.

recent coordination-driven metallacycles, such as organoplatinum acceptors assembled with aza-BODIPY ligands, combine NIR-triggered singlet-oxygen generation with platinum chemotherapy in a single, geometrically defined molecule (Li et al., 2026a). The comparative physicochemical properties, payloads, and theranostic modalities of representative cores are compiled in Table 1.

2.3 Membrane–core fusion technologies

Turning isolated membrane sheets into a uniform coating relies on mechanical, acoustic, or electrical assembly, each with its own trade-offs (Table 3) (Muhammad et al., 2026; Zhou et al., 2025). Mechanical extrusion co-extrudes cores and vesicles through track-etched polycarbonate filters of decreasing pore size; shear forces drive the bilayer to wrap the core, producing monodisperse particles that preserve native protein orientation, though filter fouling and low throughput limit scalability (Van Deun et al., 2020; Zhu et al., 2022). Ultrasonic cavitation uses acoustic energy to drive spontaneous bilayer self-assembly—fast and higher-volume, but prone to local heating that can denature receptors or push polymer cores past their glass transition (Yang et al., 2021). Microfluidic electroporation applies transient electrical pulses to permeabilize vesicles within focused flow streams, achieving coverage above 90% with high reproducibility, while sequential low-shear mixing spreads delicate exosomal membranes without thermal damage (Rao et al., 2017; Zhou et al., 2025).

2.4 Cell-membrane donors and molecular signatures

The biological fate, organ tropism, and therapeutic efficacy of a coated particle are governed by the cellular source of its cloak (Table 2, Figure 3) (Muhammad et al., 2026; Zhou et al., 2025). The sections below summarize the dominant donor classes and the surface machinery each contributes.

2.4.1 Erythrocyte membranes

Erythrocytes are the classic stealth donor (Hu et al., 2011; Xia et al., 2019). With a natural lifespan of 100–120 days, they carry a dense CD47 “marker of self” and complement regulators including decay-accelerating factor (CD55), CD59, and complement receptor 1 (CR1), which together dampen alternative complement activation (Oldenborg et al., 2000; Zhou et al., 2025). Wrapping polymeric or metallic cores in these envelopes extends circulation from hours to dozens of hours; the trade-off is a lack of intrinsic homing receptors, so targeting depends on passive extravasation or secondary ligand engineering (Li et al., 2026b; Zhou et al., 2025).

2.4.2 Platelet membranes

Platelet membranes are enriched in P-selectin (CD62P), integrin complexes (αIIbβ3/CD41/CD61), and glycoprotein VI, which bind exposed subendothelial collagen and von Willebrand factor and recognize CD44 on activated endothelium and circulating tumor cells (Hu et al., 2015; Muhammad et al., 2026). Platelet-camouflaged particles have therefore been applied to vascular injury, atherosclerotic plaque, metastatic niches, and anti-inflammatory delivery in rheumatoid arthritis (Li et al., 2021; Su et al., 2026).

2.4.3 Leukocyte, macrophage, and neutrophil membranes

Leukocyte coatings confer inflammatory tropism and barrier-crossing ability (Parodi et al., 2013; Zhou et al., 2025). Macrophage membranes retain CCR2 and CXCR4 alongside scavenger receptors and integrins, letting particles follow chemokine gradients toward inflamed, infected, or hypoxic tumor tissue, and they act as cytokine sponges that neutralize TNF-α, IL-6, and IL-1β to quiet cytokine storms in sepsis, pancreatitis, and fibrosis (Gao et al., 2020; Jiang et al., 2022; Shi et al., 2025). Neutrophil membranes display β2 integrins (CD11b/CD18) and CXCR2 that mediate rolling and firm adhesion to ICAM-1 and VCAM-1 on activated endothelium, enabling transit across the BBB and homing to ischemic or injured lung tissue (Muhammad et al., 2026; Zhang et al., 2018; Zhao et al., 2024).

2.4.4 Cancer-cell membranes

Membranes from cultured cancer cells preserve the parent line’s antigenic spectrum, including EpCAM, N-cadherin, galectins, and CD44 (Chen et al., 2016; Sun et al., 2017). These homologous adhesion molecules drive homotypic self-recognition, concentrating cancer-cell-membrane-coated particles within parent tumors, while retained tumor-associated antigens and MHC molecules allow the particles to act as personalized nanovaccines that prime cytotoxic T-cell responses (Fang et al., 2014; Fontana et al., 2018; Zhou et al., 2025).

2.4.5 Engineered hybrid membranes

To escape the functional trade-offs of any single source, researchers fuse two or more membranes by co-extrusion,

Figure 1. Top-down cell-membrane coating: from donor cell to core–shell nanoplatform. A source cell is lysed and purified—by hypotonic lysis or nitrogen cavitation followed by gradient centrifugation—to yield closed plasma-membrane vesicles that retain the cell's native surface proteins (A). In parallel, a synthetic core is fabricated from polymeric (PLGA, polydopamine, cyclodextrin), inorganic (SPION, gold, copper sulfide, bismuth selenide), metallacycle, or cubosome building blocks to carry drug and imaging cargo (B). Membrane vesicles and cores are then fused by mechanical extrusion, ultrasonic cavitation, or microfluidic electroporation/low-shear mixing to form a core–shell particle that displays surface proteins in their native right-side-out orientation (C). The resulting nanoparticle inherits prolonged circulation, immune evasion, disease-specific homing, and multimodal theranostic capability from its cellular cloak.

Figure 2. The CD47–SIRPα “don't-eat-me” inhibitory signaling axis. A biomimetic nanoparticle that inherits dense CD47 from its donor membrane (typically erythrocyte) presents this “marker of self” to SIRPα receptors on host macrophages. Receptor engagement phosphorylates the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within the SIRPα cytoplasmic tail, recruiting and activating the phosphatases SHP-1 and SHP-2. The ensuing dephosphorylation cascade blocks assembly of non-muscle myosin-IIA at the phagocytic synapse and halts actin remodeling, so engulfment is suppressed. The net effect is inhibition of macrophage phagocytosis and a corresponding extension of systemic circulation, the central mechanism underlying erythrocyte-based nanoparticle stealth.

sonication, or microfluidic mixing (Dehaini et al., 2017; Muhammad et al., 2026). Erythrocyte–cancer hybrids combine CD47-driven circulation with homotypic tumor homing (Jiang et al., 2019), while macrophage–cancer hybrids merge inflammatory chemotaxis, BBB traversal, and glioblastoma targeting for image-guided radioimmunotherapy (Yun et al., 2026; Zhang et al., 2026).

2.5 Immune evasion and protein-corona modulation

The extended circulation of these particles rests on molecular signaling that overrides immune recognition (Fadeel, 2022; Muhammad et al., 2026). The central mechanism is the CD47–SIRPα axis (Figure 2). When surface CD47 engages SIRPα on a macrophage, it triggers phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the SIRPα tail, recruiting SHP-1 and SHP-2 phosphatases; the resulting dephosphorylation cascade prevents non-muscle myosin-IIA from assembling at the phagocytic synapse, so actin remodeling stalls and engulfment is suppressed (Oldenborg et al., 2000; Tsai et al., 2010; Zhu et al., 2022).

A biological cloak does not abolish the protein corona so much as rewrite it (He et al., 2026; Yun et al., 2026). On bare synthetic surfaces, opsonins—IgG, complement C3b, fibrinogen—deposit and engage complement and Fc receptors on hepatic and splenic macrophages, accelerating clearance (Chennamsetty et al., 2026; Papini et al., 2020). Membrane coatings shift this equilibrium toward dysopsonins such as albumin and apolipoproteins, while surface glycans and sialic acids raise a steric hydration barrier against complement (Muhammad et al., 2026; Oldenborg et al., 2000). The corona remains dynamic, however: inflammation and altered metabolic states can enrich particular apolipoproteins, mask targeting ligands, and redirect biodistribution toward clearance organs (Shaw et al., 2025; Tang et al., 2023).

2.6 Multifunctional theranostic integration

By housing a therapeutic agent and an imaging probe in one membrane-cloaked architecture, biomimetic carriers support non-invasive diagnosis alongside spatiotemporally controlled therapy (Chennamsetty et al., 2026; Ma et al., 2025; Zhu et al., 2022). On the imaging side, SPION, iron-functionalized polydopamine, or gadolinium/manganese matrices sharpen MRI contrast, with some copper/manganese silicate systems switching T2-to-T1 contrast on exposure to tumor glutathione (Liu et al., 2019; Su et al., 2026); encapsulated indocyanine green or aggregation-induced-emission luminogens extend fluorescence and PA windows (Li et al., 2020; Zheng et al., 2020); and radiolabeling supports quantitative SPECT/PET tracking (Zhang et al., 2026). On the therapeutic side, NIR-absorbing cores drive PTT and immunogenic cell death, photosensitizers generate reactive oxygen species for PDT, and Fenton-active metals enable CDT; combined with checkpoint blockade, these danger signals can convert a cold tumor into an immunologically active one (Li et al., 2026a; Lin et al., 2025; Pei et al., 2018). Representative preclinical theranostic systems and their in vivo performance are collated in Table 4.

3. Methods

This article is a structured narrative review. Because the literature on biomimetic cell-membrane-coated nanoparticles (CMNPs) is mechanistically heterogeneous and spans materials science, immunology, and pharmaceutics, a narrative synthesis was chosen over a quantitative meta-analysis; nonetheless, the search, screening, and extraction steps were pre-specified and documented so that the review can be reproduced and updated (Muhammad et al., 2026; Zhou et al., 2025). The procedure below is reported at a level of detail consistent with reproducible biomedical reviewing.

3.1 Information sources and search strategy

Three bibliographic databases were queried: PubMed/MEDLINE, Scopus, and Clarivate Web of Science Core Collection. Searches combined controlled vocabulary and free-text terms across three concept blocks joined with the Boolean operator AND, with synonyms within each block joined by OR: (i) carrier—“cell membrane coating” OR “cell-membrane-coated nanoparticle” OR “biomimetic nanoparticle” OR “membrane camouflage” OR “core–shell nanoparticle”; (ii) biological source—“erythrocyte” OR “red blood cell” OR “platelet” OR “leukocyte” OR “macrophage” OR “neutrophil” OR “cancer cell” OR “stem cell” OR “bacterial outer membrane vesicle” OR “hybrid membrane”; and (iii) function—“drug delivery” OR “theranostic” OR “immune evasion” OR “protein corona” OR “photothermal” OR “photodynamic” OR “radioimmunotherapy” OR “blood–brain barrier.” Searches were restricted to peer-reviewed English-language records and were last executed before manuscript preparation; reference lists of key reviews were hand-searched to capture records missed by database indexing (Chennamsetty et al., 2026; Muhammad et al., 2026; Zhu et al., 2022).

3.2 Eligibility criteria

Records were eligible if they (a) reported original fabrication, characterization, or in vitro/in vivo evaluation of a cell-membrane-coated or hybrid-membrane nanoparticle, or (b) provided mechanistic, methodological, or translational analysis directly relevant to such systems. Primary studies were prioritized for data extraction, while authoritative reviews were retained for conceptual framing and cross-checking. Records were excluded if they addressed non-membrane stealth coatings alone (e.g., PEGylation without a biological membrane), reported insufficient methodological detail to interpret the coating step, or were conference abstracts, editorials, or non-English records without an accessible full text.

3.3 Study selection

Retrieved records were de-duplicated and screened in two stages—title/abstract, then full text—against the criteria above. Studies advancing to synthesis were grouped by the dimension they best informed: synthetic-core design, membrane isolation and purification, membrane–core fusion, immune-evasion mechanism, donor-specific tropism, theranostic modality, or translational and regulatory consideration. This mapping allowed each study to contribute to the most relevant comparative table rather than being forced into a single category.

3.4 Data extraction and quality considerations

For each primary study, the following were extracted where reported: synthetic core material and architecture; donor cell type and membrane isolation route; fusion method and critical process parameters (pore-size steps and cycle number for extrusion; amplitude, power, and temperature control for sonication; field strength, flow rate, and core-to-membrane ratio for microfluidic electroporation); coating completeness and topological orientation; particle size, polydispersity, and zeta potential; payload and release trigger; imaging and therapeutic modality; animal model; and reported pharmacokinetic or efficacy endpoints. Methodological rigor was appraised qualitatively, with attention to whether membrane purity, right-side-out orientation, and residual nucleic-acid or endotoxin content were verified, since these attributes determine both reproducibility and biosafety (Liu et al., 2021; Muhammad et al., 2026).

3.5 Synthesis, tables, and figures

Extracted data were synthesized narratively and consolidated into four comparative matrices: synthetic and inorganic cores (Table 1), biological membrane donors and their molecular signatures (Table 2), bioengineering technologies for isolation and assembly (Table 3), and preclinical theranostic applications with their translational bottlenecks (Table 4). Four schematic figures were constructed de novo to integrate the extracted mechanisms: the top-down coating workflow and core–shell architecture (Figure 1), the CD47–SIRPα inhibitory signaling axis (Figure 2), the donor-specific marker-to-tropism map (Figure 3), and the translational-bottleneck framework (Figure 4). All quantitative values reproduced in the text and tables are reported as stated in the primary sources; no new experimental data were generated for this review.

4. Cell Membrane Cloaking Reassigns Biological Fate in Theranostic Nanoparticles but Faces Translational Barriers

Read together, the studies surveyed here point to a fairly specific claim—that cloaking a synthetic core in a natural membrane does not so much improve a single property as reassign responsibility for the particle’s biological behavior. The core still dictates what is carried and what can be imaged; the shell, more often than not, decides how long the particle lasts and where it ends up. The findings below are organized around that split, moving from the core outward to the membrane, then to the assembly step, the integrated theranostic performance, and finally the barriers that keep recurring.

4.1 Physicochemical specialization and payload dynamics of the core

Across delivery models, the inner core behaves as a versatile template that sets encapsulation capacity, degradation timeline, and responsiveness to microenvironmental triggers (Table 1) (Chennamsetty et al., 2026; Li et al., 2026b). Polymeric and supramolecular matrices tend to be the workhorses: PLGA reliably achieves high loading of hydrophobic drugs and senolytics such as ABT-263, with sustained, ester-hydrolysis-controlled release over roughly 7–14 days (Jan et al., 2023; Su et al., 2026), and cyclodextrin nanosponges improve the solubility of labile compounds like curcumin and camptothecin while lowering cardiotoxicity (Garg et al., 2024). Discrete organoplatinum metallacycles are a

Figure 3. Cell-membrane donors, signature surface markers, and disease tropism. Each panel pairs a membrane donor with the characteristic surface markers it contributes (upper) and the representative biomedical target that those markers program (lower). Erythrocyte membranes supply CD47 and complement regulators for long circulation; platelet membranes provide P-selectin and glycoprotein complexes for vascular and metastatic targeting; macrophage and neutrophil membranes contribute chemokine receptors and integrins for inflammatory and barrier-crossing tropism; cancer-cell membranes exploit homotypic adhesion molecules for tumor homing and nanovaccination; and engineered hybrids combine complementary signatures for multimodal targeting and blood–brain-barrier traversal. The figure illustrates that the cellular source, rather than the synthetic core, dictates the biointerfacial mechanism and organ tropism of the particle.

Figure 4. Translational bottlenecks of biomimetic cell-membrane-coated nanotherapeutics. The barriers to clinical translation cluster into three interdependent pillars. Engineering and scale-up challenges include high-throughput GMP fabrication, continuous-flow microfluidics, lyophilization and cryo-storage, and multi-liter reproducibility. Critical quality attributes encompass right-side-out membrane topology, coating completeness above 90%, batch-to-batch consistency, and control of residual host DNA and protein content. Safety and regulatory hurdles span clearance of oncogenic DNA/RNA, attenuation of bacterial lipopolysaccharide, avoidance of alloantigen sensitization, and the ambiguous “combination product” classification. Resolving all three pillars—through standardized CQAs, closed-system biomanufacturing, and harmonized regulatory frameworks—is the prerequisite for clinical translation.

newer entry—they fold chemotherapy and an NIR photosensitizer into one molecule and resist premature burst release (Li et al., 2026a).

Inorganic and catalytic cores add something the polymers cannot: active contrast and on-demand chemistry. Iron-functionalized polydopamine and copper/manganese silicate nanospheres degrade in the glutathione-rich, acidic tumor interior, releasing cargo and, in the silicate case, generating cytotoxic hydroxyl radicals through Fenton-like catalysis (Bigaj-Józefowska et al., 2023; Liu et al., 2019). SPIONs and plasmonic gold do double duty—magnetic homing and photothermal conversion under NIR-I/II illumination (Deng et al., 2022; Su et al., 2026). A smaller but intriguing body of work uses liquid-crystalline cubosomes to co-encapsulate an antioxidant and a caged optical probe for oxidative-stress-triggered reporting in renal injury, with strikingly low background signal (Wu et al., 2026).

4.2 Biointerfacial tropism and immune evasion across donors

If the core is where the chemistry lives, the membrane is where the biology is decided (Table 2, Figure 3) (Muhammad et al., 2026; Zhou et al., 2025). The clearest, most reproducible effect in the whole literature is the erythrocyte-driven extension of circulation: RBC-coated particles move from under two hours for a naked polymeric core to well over 24–40 hours, an effect traceable to CD47 engaging SIRPα and the downstream block on myosin-IIA assembly (Figure 2) (Hu et al., 2011; Oldenborg et al., 2000; Xia et al., 2019). Complement regulators CD55 and CD59 reinforce the effect by quieting the alternative pathway (Muhammad et al., 2026).

Platelet cloaks tell a different story—less about hiding and more about finding. Through P-selectin and glycoprotein complexes they bind CD44 on circulating tumor cells and exposed subendothelial collagen, and preclinical reports describe several-fold increases in accumulation at damaged endothelium, plaque, and metastatic niches relative to bare carriers (Hu et al., 2015; Kunde & Wairkar, 2021). Myeloid coatings go further still: macrophage membranes navigate CCL2/CXCL12 gradients and double as cytokine decoys that strip TNF-α, IL-1β, and IL-6 out of the surrounding fluid (Gao et al., 2020; Jiang et al., 2022), while neutrophil membranes exploit β2 integrins to cross the BBB and the alveolar–capillary interface (Wang et al., 2021; Zhang et al., 2024). Cancer-cell and hybrid membranes, meanwhile, trade on homotypic adhesion and, in the hybrid case, combine prolonged circulation with multivalent, multi-barrier targeting (Dehaini et al., 2017; Jiang et al., 2019; Zhang et al., 2026).

4.3 Biophysical quality attributes and assembly engineering

The fabrication step turns out to matter at least as much as the choice of membrane, and the comparison across methods is not flattering to any single technique (Table 3) (Muhammad et al., 2026; Zhou et al., 2025). Extrusion through track-etched filters gives monodisperse particles (PDI < 0.15) and reliably preserves right-side-out orientation, but it fouls, scales poorly, and throws away most of the membrane input—often retaining only 5–15% (Hu et al., 2011; Van Deun et al., 2020). Sonication is faster and higher-volume, yet uncontrolled heating risks denaturing receptors and pushing PLGA past its glass transition into irreversible aggregation (Yang et al., 2021). Microfluidic electroporation looks, on current evidence, like the most promising route—coating completeness above 90%, high reproducibility, and preserved protein accessibility—while low-shear microfluidic mixing spreads fragile exosomal membranes without degrading sensitive probes (Rao et al., 2017; Wu et al., 2026).

Upstream of assembly, the lysis method shapes safety. Hypotonic lysis suffices for non-nucleated erythrocytes, whereas nucleated cells generally require nitrogen cavitation—pressurization to roughly 350–400 psi followed by rapid decompression—to rupture the plasma membrane while leaving nuclei intact (Li et al., 2026b; Muhammad et al., 2026). Pairing cavitation with a 30–40% sucrose density gradient then removes chromatin, mitochondria, and genomic DNA, which is less a refinement than a prerequisite for translational safety (Muhammad et al., 2026).

4.4 Integrated theranostic performance in preclinical models

When these pieces come together, the preclinical results are, frankly, impressive—though it is worth noting they are almost entirely in rodents (Table 4). In hepatocellular carcinoma and breast-cancer models, cancer-membrane-coated iron-functionalized polydopamine delivered strong T1/T2 MRI contrast alongside efficient photothermal conversion, with 808-nm irradiation driving localized hyperthermia above ~48 °C and, in some reports, complete primary-tumor regression without overt systemic

toxicity (Bigaj-Józefowska et al., 2023). HeLa-membrane-cloaked platinum metallacycles produced singlet oxygen and heat that exposed calreticulin and released HMGB1; paired with anti-PD-L1 blockade, this biomimetic photoimmunotherapy drove CD8⁺ T-cell infiltration against both primary and distant tumors (Li et al., 2026a). In gastric cancer, ¹³¹I-labeled macrophage–cancer hybrid liposomes enabled SPECT imaging while delivering targeted radioimmunotherapy (Zhang et al., 2026).

The non-oncologic examples are, in some ways, the more surprising ones. Macrophage-camouflaged magnetic nanoparticles carrying ABT-263 combined magnetic guidance with CCR2-mediated homing to clear senescent macrophages and halt aberrant vessel ingrowth in a spinal endplate-sclerosis model (Su et al., 2026), and exosome–cubosome hybrids loaded with lipoic acid provided real-time fluorescent reporting of reactive oxygen species while limiting oxidative damage in renal ischemia–reperfusion injury (Wu et al., 2026). Taken as a set, these studies suggest the platform’s reach extends well beyond oncology, even if the evidence outside cancer is still thin.

4.5 Recurring translational barriers and critical quality attributes

What is striking, reading across otherwise unrelated papers, is how the same four obstacles keep surfacing (Figure 4). First, topological inversion: when vesicles flip inside-out during processing, the extracellular domains of CD47 and targeting receptors end up buried against the core, and cryo-TEM plus functional assays show that even partial core exposure can redirect biodistribution toward clearance organs (Liu et al., 2021). Second, biological heterogeneity—variable surface-protein expression and membrane-to-core ratios across runs—which makes standardized CQAs such as residual host-cell DNA (< 10 ng/dose) and endotoxin limits (< 5 EU/kg) essential rather than optional (Chennamsetty et al., 2026; Shan et al., 2026). Third, colloidal and storage instability, where formulations without optimized cryoprotectants (typically 5–10% trehalose or sucrose) lose integrity on freeze-drying (Li et al., 2026b). And fourth, the regulatory tangle of “combination product” status, which spreads oversight across biological, pharmaceutical, and imaging divisions and, for now, lacks a harmonized international standard (Liu et al., 2026).

5. Moving Cell Membrane-Coated Nanoparticles From Proof of Concept to Manufacturable, GMP-Ready Medicines

5.1 What the evidence consistently supports

It is tempting, given the volume of positive reports, to treat cell-membrane coating as a solved problem. The more careful reading is narrower. What the literature supports with real consistency is a single proposition: a natural membrane can hand a synthetic particle a biological identity that the innate immune system is slow to challenge, and that identity—not the core—largely governs circulation and homing (Fadeel, 2022; Muhammad et al., 2026; Zhou et al., 2025). The erythrocyte-CD47 effect is the strongest pillar here, reproduced across cores and laboratories and mechanistically well explained by the SIRPα cascade (Figure 2) (Oldenborg et al., 2000; Tsai et al., 2010). Much of the rest of the field is built, reasonably, on the inference that if one membrane transfers its function, others should too—and in most cases they appear to.

5.2 The corona is reshaped, not erased

One finding deserves more emphasis than it usually gets: coating does not give a particle a clean, protein-free surface. It changes which proteins arrive (He et al., 2026; Yun et al., 2026). That distinction matters because it reframes the design target. If the goal were simply to prevent adsorption, a better inert polymer might suffice; but if the real mechanism is a shift from opsonins toward dysopsonins like albumin and apolipoproteins, then the membrane’s glycan and sialic-acid landscape becomes a design parameter in its own right (Muhammad et al., 2026; Papini et al., 2020). The uncomfortable corollary is that the corona stays dynamic. Under inflammation or hypercholesterolemia, apolipoprotein enrichment can mask the very ligands the coating was meant to display, quietly redirecting particles toward the liver and spleen (Shaw et al., 2025; Tang et al., 2023). A particle validated in a healthy animal may therefore behave differently in diseased tissue—a caveat that rarely makes it into efficacy summaries.

5.3 The orientation and completeness problem

If there is a single under-appreciated failure mode, it is probably membrane orientation (Figure 4). A coating can look complete by size and zeta potential and still be functionally inert if a meaningful fraction of its vesicles sealed inside-out, burying CD47’s extracellular loops where no macrophage will ever see them (Bu et al., 2021; Liu et al., 2021). The same is true of incomplete coverage: a patch of exposed core is enough to seed opsonin deposition and shift the internalization pathway (Liu et al., 2021; Muhammad et al., 2026). This is where fabrication choice stops being a convenience and becomes a determinant of efficacy—extrusion preserves orientation but will not scale, sonication scales but risks damage, and microfluidic routes currently offer the best, though not yet fully industrialized, compromise (Rao et al., 2017; Van Deun et al., 2020). It is hard to escape the sense that the field’s next real gains will come from the assembly line rather than from new biology.

5.4 Heterogeneity, safety, and the limits of biological sourcing

Biological sourcing is simultaneously the platform’s greatest strength and its most stubborn liability. Donor genetics, passage number, and culture conditions all perturb membrane composition, so batch-to-batch variability is not a manufacturing nuisance to be engineered away but an intrinsic feature of using living material (Chennamsetty et al., 2026; Li et al., 2026b). Safety concerns compound this. Cancer-cell membranes raise the specter of transferring oncogenic DNA or microRNA and demand rigorous validation (Muhammad et al., 2026); bacterial outer-membrane vesicles carry lipopolysaccharide that must be attenuated, for instance by msbB deletion, to avoid endotoxin shock (Chen et al., 2020); and repeated dosing of allogeneic membranes bearing non-self MHC can provoke anti-membrane antibodies and accelerated clearance (Larssen et al., 2019). None of these is necessarily disqualifying, but each converts an elegant idea into a demanding quality-control exercise.

5.5 Toward standardized, GMP-compliant translation

Where does this leave the path to the clinic? Mostly, it argues for a change of emphasis—from discovery to process (Table 4, Figure 4). Continuous-flow, closed-system microfluidics capable of multi-liter throughput under current GMP is the most frequently cited enabling technology, and for good reason: it addresses orientation, reproducibility, and scale at once (Cardellini et al., 2025; Li et al., 2026b). Genetic engineering of donor cells to overexpress targeting ligands while knocking out immunogenic alloantigens offers a way to make membranes more uniform and less reactive by design (Zhou et al., 2025). Standardized, non-destructive assays for corona evolution and receptor accessibility would let manufacturers release product against meaningful specifications rather than surrogate ones (He et al., 2026). And refined lyophilization with trehalose or sucrose cryoprotectants is the unglamorous but necessary step toward an off-the-shelf product (Shan et al., 2026). None of this is conceptually novel; all of it is hard, and most of it is where the field now needs to spend its effort.

5.6 Limitations of the current evidence base

Finally, a note of restraint. The preclinical record is overwhelmingly rodent-based, short-term, and reported by the groups developing the platforms; head-to-head comparisons under standardized conditions are scarce, and negative results are almost certainly under-published. Quantitative claims—circulation half-lives, fold-changes in tumor accumulation—vary with model, dose, and analytical method and should be read as indicative rather than definitive (Zhang et al., 2023; Zhu et al., 2022). This review inherits those limitations: as a structured narrative synthesis rather than a meta-analysis, it integrates heterogeneous studies without pooling them statistically. The pattern it describes is, we think, robust; the individual numbers are not where the confidence lies.

6. Conclusion

Biomimetic cell-membrane coating has matured from a clever laboratory trick into a coherent engineering philosophy—one that borrows the immune fluency of living cells instead of trying to synthesize it from scratch. Across the studies surveyed here, a consistent pattern emerges: the synthetic core sets the payload and the imaging signal, while the biological shell decides how long the particle survives and where it ultimately goes. That division of labor explains both the platform's versatility and its fragility, because the very membranes that confer stealth and homing are also the hardest components to source, orient, and preserve reproducibly. The decisive question, then, is no longer whether these nanoparticles work in animals—they clearly do—but whether they can be made the same way twice at clinical scale. Progress will depend on continuous-flow manufacturing, genetically tailored membranes, standardized critical quality attributes, and regulatory frameworks designed for genuinely hybrid products rather than retrofitted from older categories.

References