2025 Volume 7 Issue 1 Pages 30-36
Surface bio-engineering of polymeric nanoparticles (PNPs) represents a pivotal advancement in modern biomedical research, offering transformative potential for diagnostics, therapeutic interventions, and drug delivery. This approach focuses on functionalizing PNP surfaces with bioactive moieties, enabling precise and targeted interactions with biological systems. Despite its promise, several challenges hinder the clinical translation of surface-bioengineered PNPs. These include achieving precise control over surface modifications, maintaining stability within biological environments, and ensuring sustained, targeted interactions with cells and tissues. Furthermore, issues related to scalability, reproducibility, and long-term safety complicate their widespread adoption in medical applications. This review explores recent advancements in the design and application of surface-biofunctionalized PNPs, encompassing their use in biosensing, bioimaging, and targeted therapeutic delivery. Emphasis is placed on the molecular mechanisms driving the attachment of bioactive entities to PNP surfaces and their impact on nanoparticle stability and efficacy in both in vitro and in vivo systems. Current obstacles, such as limited control over functionalization processes and challenges in ensuring consistency across manufacturing scales, are critically analyzed. Finally, potential solutions and future research directions to overcome these barriers are discussed, highlighting the transformative possibilities of surface-bioengineered PNPs in addressing complex biomedical challenges.
Surface bio-engineering of polymeric nanoparticles (PNPs) offers groundbreaking potential in diagnostics, drug delivery, and therapies, yet faces challenges like stability, scalability, and safety. This review critically examines recent advancements, molecular mechanisms, and solutions to enhance their biomedical applications.
Nanotechnology is at the forefront of global efforts to address sustainability challenges, aligning with the United Nations’ Decade of Action to achieve Sustainable Development Goals (SDGs) by 2030. Among these goals, nanoparticles are playing a critical role in advancing “Good Health and Well-Being” by offering innovative solutions in medicine. Engineered nanoparticles exhibit diverse properties, such as opto-magnetic, catalytic, and pharmacokinetic capabilities, making them invaluable for applications in precision medicine, diagnostics, and therapeutics. Polymeric nanoparticles (PNPs), in particular, stand out due to their flexible polymeric structure, which allows for stable dispersions, high drug-loading capacity, and compatibility with biological systems. These features make PNPs ideal for bioimaging, targeted cancer therapies, and other biomedical applications.
Surface functionalization of PNPs with bioactive molecules, or “biofunctional molecules”, is a key strategy for enhancing their biological performance. These molecules, which include organic compounds, polymers, and biomolecules such as proteins and DNA, can be tethered to nanoparticle surfaces to induce specific cellular responses. Functionalized nanoparticles can act as biosensors, detect reactive oxygen species (ROS), or serve as imaging agents for tumor recognition. Surface modifications using hydrophilic polymers like polyethylene glycol (PEG) or polysaccharides can prolong circulation time by evading immune detection, while tumor-targeting ligands, such as antibodies or aptamers, enhance specificity and cellular uptake. The careful selection and functionalization of PNP surfaces are essential for achieving desired properties, optimizing performance, and ensuring success in biomedical applications [1].
Nanoparticles in cellular environments trigger biological responses, either recognizing them as compatible or targeting them for removal. Surface functionalization can modulate these interactions, preventing immune clearance. Functionalization methods are broadly categorized into non-covalent and covalent approaches, differing in bond type and strength. This section outlines these strategies, explaining their mechanisms and evaluating their benefits and limitations. Non-covalent attachment, or physisorption, relies on weak interactions such as van der Waals forces, hydrogen bonds, and electrostatic interactions. For instance, oppositely charged surfaces can immobilize molecules without complex preparation or linker chemistry. An example is the electrostatic attachment of anti-HER2 antibodies to positively charged chitosan (-NH3+) on PLGA nanoparticles loaded with Doxorubicin. However, the non-covalent nature of these bonds makes them susceptible to displacement by biomolecules with higher surface affinity, a phenomenon known as the Vroman effect, which can compromise conjugate stability. Covalent functionalization offers a more robust alternative by forming strong chemical bonds between nanoparticles and biofunctional molecules. This approach, often achieved through wet-chemical methods, involves using linkers or introducing functional groups on the nanoparticle surface to anchor the desired molecules. Covalent bonds ensure greater stability and durability, making them suitable for applications requiring long-term functionality. Introducing linker or spacer molecules is a well-established method to enhance the binding of functional groups to nanoparticle surfaces. For instance, DNA probes have been designed using amine-polyethylene glycol (PEG)-azide linkers to facilitate DNA aptamer attachment on carboxylated polystyrene nanoparticles, enabling stable and specific detection of proteins like VEGF. While PEG and silane are commonly used as carbon-chain linkers, natural derivatives such as dopamine and chitosan provide diverse surface chemistries for covalent functionalization [2].
Direct covalent conjugation, relying on nanoparticle surface reactive groups, offers an alternative to using linkers. Functional groups like amines (-NH2) or carboxyls (-COOH) allow direct biomolecule attachment. For example, aminosilanes functionalize silica nanoparticles, while thiol (-SH) or amine (-NH2) groups are used to modify gold nanoparticles. Carbodimide-based coupling is widely employed for attaching proteins, fluorophores, or antibodies, enhancing nanoparticle utility in diagnostics and therapy. Advances in site-selective chemistries, such as maleimide and vinyl sulfone conjugation, improve ligand orientation and enhance antigen binding, although challenges remain in controlling environmental conditions and minimizing nonspecific interactions. Wet-chemical approaches for covalent attachment, despite their effectiveness, involve multiple complex steps, including polymer preparation, functionalization, and purification. For instance, PEGylation of nanoparticles requires numerous reagents and incubations, increasing time and cost. These processes often require harsh solvents and elevated temperatures, posing safety risks and environmental concerns. Plasma-based techniques offer a sustainable alternative to wet-chemical methods, enabling reagent-free nanoparticle synthesis and functionalization. Plasma processes, involving ionized gases and radical fragmentation, create reactive surfaces for biomolecule immobilization in a single step. Plasma polymerization, originally explored as by-products in the semiconductor industry, is now recognized for its biomedical potential. These techniques enable efficient, eco-friendly surface modifications, making them a promising tool for advancing nanoparticle applications in biomedicine [3].
The development of highly sensitive small-scale biosensors is crucial for biomedical and environmental applications. These sensors typically consist of a recognition element that binds specifically to target analytes and a transducer that converts this binding into an electrochemical, colorimetric, or fluorescent signal. Polymeric nanoparticles (PNPs) provide an ideal platform for biosensing due to their customizable physicochemical properties and ability to be functionalized with specific groups. This makes them effective as both recognition and signaling components in biosensor systems. These systems are vital for accurately detecting physiological changes, such as pH, reactive oxygen species (ROS), and small biological agents, helping to monitor cellular health, prevent organ system damage, and address global biological threats [4].
ROS Sensors: Reactive oxygen species (ROS) are natural byproducts of oxygen metabolism and play a vital role in cellular signaling and organismal growth. However, excessive ROS levels, such as hydrogen peroxide (H2O2), can lead to oxidative stress, destabilizing proteins and causing cellular damage. This disruption is linked to various diseases, including neurodegenerative disorders, cardiovascular diseases, and cancers. As a result, significant research has focused on detecting and monitoring ROS, especially H2O2, in living cells. Electron spin resonance (ESR) is a traditional technique for ROS detection, relying on unpaired electrons in molecules. However, H2O2 lacks an unpaired electron, making direct detection challenging. This requires the use of spin-trapping probes to generate detectable radicals through redox reactions, which limits specificity and sensitivity in vivo, as well as increasing the cost and complexity of the method. Polymeric nanoparticles (PNPs) have gained attention as fluorescent probes for ROS detection due to their solubility, long circulation time, and compatibility with biological environments. Surface modifications on PNPs enhance their versatility, allowing them to specifically detect H2O2. Boronate-based fluorescent probes, for example, offer high specificity and contrast for H2O2 sensing at physiological concentrations. A widely used detection method involves fluorescence resonance energy transfer (FRET), where compounds like 7-hydroxycoumarin (HC) and 4-carboxy-3-fluorophenylboronic acid (FPBA) bound to nanoparticles undergo FRET, producing a new fluorescence peak. In the presence of H2O2, the fluorescence intensity at 600 nm decreases, while the intensity at 450 nm increases, providing a selective and sensitive readout for H2O2 levels. Another approach utilizes photo-induced electron transfer (PET) to detect H2O2. For example, boronate-modified polyacrylonitrile (BPAN) nanoparticles undergo PET upon exposure to H2O2, causing changes in fluorescence intensity and emission peaks. This method has been successfully tested in vitro using RAW264.7 macrophage cells, where BPAN nanoparticles detected elevated H2O2 levels due to oxidative stress. These results demonstrate the potential of PNPs as non-toxic, effective tools for monitoring ROS in biological systems [5].
PH Sensors: Intracellular pH plays a crucial role in various cellular processes, including metabolism, enzyme activity, and protein folding. Abnormal pH levels are linked to diseases like cancer and Alzheimer’s. Recently, pH nanosensors have emerged as effective tools to measure intracellular pH, offering advantages such as high signal intensity, rapid response, and ease of modification. Fluorescent nanosensors, which operate based on changes in fluorescence intensity, are commonly used for pH measurement. These sensors can either brighten (turn-on) or dim (turn-off) in response to pH changes. However, their single-emission signals are affected by environmental factors, photo-bleaching, and sensor concentration. To overcome these limitations, ratio-metric fluorescent sensing uses multiple emission wavelengths to detect environmental changes more reliably. Dual ratio-metric fluorescent sensors, which utilize two distinct emission signals, have shown promise in improving measurement accuracy. Polymeric nanoparticle (PNP)-based sensors are particularly beneficial, offering non-invasive, in-situ tracking of cellular dynamics. For example, a tunable ratio-metric fluorescent nanosensor was developed by conjugating aggregation-induced emission (AIE) dyes to the surface of hyperbranched PNPs. The system uses pH-sensitive and pH-insensitive fluorophores to monitor pH changes in HeLa cells, providing accurate intracellular pH sensing with good biocompatibility. Another approach utilizes fluorescence resonance energy transfer (FRET) between donor and acceptor dyes covalently attached to PNPs, allowing for intracellular pH visualization. These nanosensors change fluorescence from blue (low pH) to green (high pH), effectively tracking pH changes in lysosomes. Furthermore, triple-labeled nanosensors, combining pH-sensitive and reference dyes, offer a wider sensing range for more accurate pH detection, particularly in the endosome-lysosome system. Self-organizing principles in nanoparticle design, such as mixed micelles based on triblock copolymers, also enable tailored spectroscopic properties and surface targeting. Advances in designing dual- and triple-functionalized pH nanosensors have further extended the measurable pH range, allowing for more comprehensive pH monitoring in live cells. For instance, the combination of fluorophores like FITC/BCECF or Rhodamine B/Alexa 633 expands the pH sensitivity range, enhancing the ability to measure a broader range of physiologically relevant pH levels in mammalian cells. However, careful consideration is needed to optimize FRET efficiency and linearity for accurate ratio-metric measurements [6].
Bioimaging systemMolecular imaging is a diagnostic technique that allows visualization and quantification of physiological changes using imaging agents. Recent advances in molecular imaging have made it possible to monitor cellular-level variations for early disease detection. Polymeric nanoparticles (PNPs) have gained significant attention as imaging agents due to their ability to pass through cellular barriers without triggering immune responses. Their large surface area-to-volume ratio also provides a high loading capacity, enabling targeted delivery of imaging agents to specific areas. Surface functionalization of PNPs enhances their performance in imaging by improving biocompatibility, enabling multimodal imaging capabilities, and allowing the attachment of multiple targeting moieties to a single nanoparticle. These surface modifications increase their utility in various imaging techniques, including X-ray, optical imaging, and magnetic resonance imaging (MRI). PNPs have thus become versatile tools for the spatiotemporal evaluation of cellular functions and the tracking of disease biomarkers, advancing both diagnostic capabilities and therapeutic monitoring [7].
X-Ray Contrast Agents: Computed tomography (CT) is a widely used imaging technique in clinical settings, producing high-resolution 3D images using X-rays. It relies on contrast agents (CAs) that accumulate in tissues with increased vascular permeability, such as tumors, through the enhanced permeability and retention (EPR) effect. Common CT contrast agents include iodine, gold, and bismuth, while lanthanides are explored for their high atomic number, crucial for X-ray attenuation. However, small contrast molecules can be toxic at the concentrations needed and have short circulation times, limiting their clinical use. To address these issues, contrast agents are often incorporated into nanoparticles with biocompatible surface layers of hydrophilic polymers, lipids, or silica. For instance, poly-ε-caprolactone (PCL)-coated nanoparticles stabilize metallic agents like iodine in aqueous environments. Bismuth and lanthanide nanoparticles coated with polyvinylpyrrolidone (PVP) show improved X-ray attenuation compared to traditional free agents. Additionally, the use of PEGylated surfactants in lipid nanoparticles increases stability after intravenous administration. Gold nanoparticles, known for their superior CT imaging efficiency due to their high atomic number, are also explored for enhanced tumor imaging. For example, gold-functionalized nanocomposites (COP@Au@TCPP) are used for CT tumor imaging and photodynamic therapy (PDT). However, hydrophobic interactions between nanoparticles and their surface coatings can lead to the untimely release of agents, risking premature breakdown due to physiological reactions. To prevent this, covalent bonds are increasingly used to stabilize nanoparticles. Recent advancements also include the covalent attachment of iodine-labeled contrast agents to polymeric nanoparticles, such as dendrimers, to improve CT imaging stability and biocompatibility. These iodinated nanoparticles have shown great promise in enhancing tumor visibility, monitoring the distribution of photothermal agents, and supporting targeted cancer therapies. Continued research into these modified nanoparticles is advancing CT-guided cancer treatment by providing more precise imaging, enabling better tracking, and improving therapeutic outcomes.
Optical Contrast agents: Optical imaging techniques, such as fluorescence and bioluminescence, have significantly advanced disease diagnostics by enabling the visualization of subcellular biological processes in living systems. Recent innovations in optical imaging using polymeric nanoparticles (PNPs) have driven growth in molecular imaging, thanks to their non-invasive nature and the high photostability of the nanoparticles. Fluorescence imaging, in particular, benefits from optical probes with features like multi-coloring or controlled signal activation, enhancing the signal-to-background ratio. The fluorescence signal of PNPs depends on the chemical reactions between selective fluorescent agents and the particle surface. For example, energy transfer from organic tetraphenyl methane nanoparticles to surface-bound Rhodamine 6G dye molecules produces detectable green fluorescence. While physical adsorption of dyes can diminish fluorescence in physiological conditions, covalent bonding ensures the stability of fluorescent agents, as seen with near-infrared fluorescent (NIRF) dyes. NIRFs, such as cyanine dyes (e.g., Cy5, Cy5.5, Cy7), exhibit deep tissue penetration and are covalently attached to polymeric nanoparticle matrices, offering robust, long-lasting fluorescence signals. Hydrophilic dyes like AEMH-FITC also bind covalently to PNPs with amino groups on their surfaces, enabling cellular imaging, such as in HeLa cells, where they can function as specific molecular recognition tools. In this case, the surface-bound dye serves as a mercury recognition element, while a hydrophobic dye is encapsulated within the nanoparticle core, showcasing the versatility of PNPs in molecular imaging applications.
Magnetic resonance Contrast agents: Magnetic Resonance Imaging (MRI) is a widely used diagnostic tool, valued for its non-invasive nature and safety, especially for brain and central nervous system imaging, as it avoids ionizing radiation. MRI generates high-resolution 3D images by detecting differences in proton density within tissues, and contrast agents are used to enhance the visibility of tissues, especially at the cellular and molecular levels. These agents modify the proton relaxation times (T1 and T2), improving image contrast. The efficiency of contrast agents is measured by their relaxivity, which refers to their ability to alter relaxation rates and, thus, image brightness or darkness. Gadolinium-based contrast agents (GBCAs) are commonly used as T1 agents due to their optimal magnetic properties. However, the release of free Gd ions can be toxic, leading to nephrotoxicity. To mitigate this, Gd is typically chelated with compounds like DOTA or DTPA to prevent ion leakage, but these agents suffer from low stability and rapid renal clearance. Polymeric nanoparticles (PNPs) conjugated with Gd-chelates can improve the stability of Gd, concentrating it on the nanoparticle surface and enhancing MRI signal intensity. Spacer molecules like Polyethyleneimine (PEI) are used to covalently link Gd-chelating agents to the nanoparticles, improving stability and reducing toxicity. Research has shown that PNPs conjugated with Gd-DTPA and other chelating agents can achieve significantly higher relaxivity than traditional small-molecule agents like Magnevist®. For example, a PLGA-based nanoparticle coated with paramagnetic folate-functionalized PEG showed a threefold increase in longitudinal relaxivity. In vivo studies using Gd-DTPA-functionalized polyethyleneimine-grafted poly (L-lysine) nanoparticles have demonstrated high Gd loading and improved contrast in MRI imaging. These surface-functionalized PNPs show great promise for creating more effective, biocompatible, and stable contrast agents, with enhanced performance and long-term stealth in the bloodstream, making them ideal for applications such as blood pool imaging and the detection of capillary lesions [8].
Nanoparticles have gained significant attention as carriers for targeted drug delivery, offering a promising approach to direct therapeutics to diseased cells. However, one of the main challenges is the nonspecific interactions between nanoparticles and biological fluids, which can lead to unintended adhesion to blood components, disruption of blood cell morphology, and aggregation. These interactions can also trigger sequestration by the mononuclear phagocyte system (MPS), such as liver scavenger cells, limiting the efficacy of drug delivery. To overcome these challenges, nanoparticles must be engineered to minimize adverse interactions and ensure successful intravenous circulation. The surface properties of nanoparticles play a crucial role in preventing nonspecific binding and promoting targeted delivery to specific sites of pathology. Surface modifications, such as the incorporation of hydrophilic polymers or targeting ligands, enhance the stability of nanoparticles in the bloodstream and improve their ability to reach and interact with diseased cells. Over the past two decades, considerable advancements have been made in the design of surface-functionalized polymeric nanoparticles (PNPs) for targeted drug delivery and therapeutic applications, highlighting their potential for precision medicine [9].
Targeted drug deliveryThe development of effective surface-functionalized polymeric nanoparticles (PNPs) for targeted drug delivery relies on three key factors: the method of surface modification, the compatibility of the surface with the circulation environment, and the targeting ability of the functionalized nanoparticle. Various surface modification techniques, including physisorption, interfacial embedding, and dopamine polymerization, influence the structural integrity and functionality of nanoparticles. Among these, dopamine polymerization is particularly advantageous as it forms polydopamine (pD) layers, which help preserve the native conformation of bioactive molecules such as albumin. This structural preservation enhances interactions with cancer cells expressing albumin-binding proteins, facilitating improved targeting and drug delivery. In contrast, some other modification methods may lead to protein denaturation, reducing the nanoparticle’s efficacy.
Beyond albumin-functionalized systems, polydopamine-based modifications have been widely explored for conjugating cancer cell-targeting peptides onto PNPs, improving tumor specificity and cellular uptake. These peptides, such as RGD (Arg-Gly-Asp) peptides, selectively bind to integrins overexpressed on tumor cells, enhancing nanoparticle accumulation at the tumor site. Similarly, NGR (Asn-Gly-Arg) peptides target aminopeptidase N (CD13), a marker found in angiogenic tumor vasculature, aiding in both drug delivery and tumor imaging. Additionally, folate, peptides, and chitosan have been successfully immobilized onto PNPs through polydopamine coatings, further enhancing their targeting capabilities. However, despite these advantages, certain challenges remain, such as shifts in optical properties and potential nanoparticle destabilization due to the alkaline conditions required for dopamine polymerization. Addressing these concerns through optimized polymerization conditions and multi-functional nanocarrier designs could further improve the stability and effectiveness of peptide-functionalized PNPs in targeted cancer therapy [10].
To address these challenges, tannic acid (TA), a plant-derived polyphenol, has emerged as an alternative surface modifier. TA enables the attachment of thiol- or amine-terminal groups on the nanoparticle surface, facilitating effective drug loading and target-specific interactions. For example, TA-functionalized PLGA nanoparticles show high affinity for molecules like doxorubicin and folate, with drug loading efficiency improving for molecules with primary amine groups. Hydrophilic surface modifications are also crucial for the performance of PNPs, as they help avoid immune system recognition, extend circulation time, and improve targeting accuracy. Hydrophilic spacers, such as polyethylene glycol (PEG), further shield the surface from biomolecular degradation and enhance targeting specificity.
For example, in colorectal cancer therapy, PNPs coated with chitosan have demonstrated improved biodegradability, biocompatibility, and prolonged stability. The chitosan coating enhances the anticancer activity of drug-loaded nanoparticles, such as imatinib (IMT), by protecting healthy cells from drug-induced damage and providing controlled cytotoxicity to cancer cells. These findings highlight the importance of surface modification in optimizing the performance of PNPs for targeted drug delivery [11] Table 1.
| Nanoparticle | Functionalizing agent | Mechanism | Applications | In vitro studies |
|---|---|---|---|---|
| Poly (lactic-co-glycolic acid) (PLGA) + Fe3 O4+ QD | Taxol (paclitaxel), Anti-Her2 monoclonal antibodies, Fe3O4NPs and quantum dots | Fe3O4NPs and quantum dots surface attachment through amine-terminals, Anti-Her2monoclonal antibodies were immobilized on the surface of AuNR/QD/Fe3O4/Taxol-loaded PLGANPs | Tumor-targeted chemotherapy via photo thermal-control drug release with chemotherapy and photo thermal destruction | Distributed HeLa cells (cervix cancer cells) in an MTT assay effectively killed due to Taxol release. |
| Poly (lactide-co-glycolide) PLGA, Poly-ethylene glycol (PEG) spacer | Biotin and folic acid Paclitaxel cancer drug | Interfacial Activity Assisted Surface Functionalization (IAASF) | Tumor-targeted drug delivery | Molecule-conjugated nanoparticles were extensively taken up relative to free nanoparticles by different cancer cell lines with overexpressed receptors. |
| α-acetoxy-poly (ethylene glycol)-poly (d,l-lactide) block copolymer (acetal-PEG–PDLLA) | Peptidyl ligands (phenylalanine (Phe) and tyrosyl–glutamic acid (Tyr–Glu) | Transformation of the acetal groups into aldehyde groups followed by Schiff base and reductive amination | Potential drug carriers with modulated surface charge | - |
The Enhanced Permeability and Retention (EPR) effect is a key principle in nanoparticle-mediated drug delivery for cancer therapy. This phenomenon allows nanoparticles to preferentially accumulate within tumor tissues due to distinct physiological characteristics, such as abnormal vascular permeability and impaired lymphatic drainage. These attributes enable nanoparticles to passively infiltrate and persist within the tumor microenvironment, enhancing drug delivery efficiency while minimizing systemic toxicity. The mechanism of the EPR effect is primarily driven by leaky tumor vasculature, where rapid and aberrant angiogenesis results in the formation of blood vessels with enlarged endothelial fenestrations (100–800 nm in diameter). Nanoparticles within the optimal size range (10–200 nm) can traverse these vascular gaps, facilitating their passive accumulation in tumor tissues. Furthermore, reduced lymphatic clearance in tumors prevents the efficient drainage of accumulated nanoparticles, thereby prolonging drug exposure at the tumor site and improving therapeutic efficacy. The selective accumulation of nanoparticles is another critical advantage of the EPR effect, as the tight endothelial junctions in normal tissues (5–10 nm) prevent nanoparticle penetration, reducing off-target effects. This phenomenon enhances tumor selectivity, leading to improved drug localization and therapeutic precision. Various nanocarriers, including polymeric nanoparticles, liposomes, and micelles, exploit the EPR effect for efficient drug delivery. Further advancements involve surface-functionalized nanoparticles modified with specific ligands (e.g., peptides, antibodies) to enhance binding to tumor receptors and improve intracellular uptake. Additionally, controlled and sustained drug release mechanisms within these nanoparticles ensure prolonged therapeutic action at the tumor site, increasing their efficacy in targeted drug delivery.
For precise cancer therapy, nanoparticles are often surface-modified with ligands that recognize and bind to tumor-specific elements, such as pH variations and overexpressed proteins. These modifications enhance nanoparticle retention and therapeutic efficacy by promoting receptor-mediated endocytosis. Recent studies have highlighted the role of tumor-associated macrophages (TAMs) in sustaining cancer progression by activating pathways that drive cancer stem cell proliferation. To target TAMs selectively, poly (lactic-co-glycolic acid) (PLGA) nanoparticles have been functionalized with tannic acid-iron complexes and M2pep, a peptide ligand specific to M2-polarized macrophages. In a melanoma model, M2pep-functionalized nanoparticles exhibited enhanced accumulation in CD206+ macrophages, significantly outperforming uncoated nanoparticles in tumor localization. Furthermore, the encapsulation of PLX3397, a colony-stimulating factor inhibitor, within these nanoparticles resulted in superior tumor suppression compared to free-drug formulations or albumin-coated nanoparticles. Another widely studied targeting strategy involves folic acid (FA), frequently used to enhance nanoparticle selectivity toward cancer cells due to the overexpression of folate receptors (FRs) in many tumors. Photoresponsive gold-immobilized acrylic polymer nanoparticles (PGPNPs) were functionalized with FA using L-cysteine linkages, improving their tumor-targeting efficiency via receptor-mediated endocytosis. In glioma cell models (C6), FA-functionalized PGPNPs demonstrated a 2.5-fold increase in uptake compared to non-functionalized nanoparticles, highlighting their potential for targeted cancer therapy. The integration of functionalized nanoparticles with therapeutic agents has extended beyond oncology to address conditions such as respiratory infections and neurodegenerative diseases, including Alzheimer’s disease. Additionally, emerging dual-targeting strategies, image-guided therapy, and multifunctional theranostic systems are paving the way for personalized medicine approaches, optimizing treatment outcomes through precision-targeted interventions. By leveraging the EPR effect alongside advanced surface modifications, nanoparticle-based drug delivery systems continue to revolutionize cancer therapy, offering highly selective, efficient, and personalized treatment solutions [12].
While surface biofunctionalized polymeric nanoparticles (PNPs) have shown promise in diagnostics and therapeutics, their clinical translation remains limited. As of June 2021, only 10% of nanomedicines in clinical stages were polymer-based. This slow progress can be attributed to the challenges in replicating in vivo environments, where precise interactions between nanoparticle surfaces and biological media are not fully understood. Furthermore, immune responses vary across species, complicating the development of consistent in vivo models. Despite advances in surface functionalization, scaling-up production of functionalized PNPs for large-scale manufacturing remains a hurdle, with limited progress in industrial partnerships and reproducible manufacturing processes. Emerging technologies such as stem cell research, microfluidics, and organ-on-a-chip models are being explored as alternatives to traditional animal testing. In January 2023, the U.S. FDA removed animal testing requirements for new drugs, facilitating the adoption of these advanced models for testing nanoparticle-based therapies. In parallel, innovative techniques like plasma polymerization and plasma treatment of nanoparticles are gaining traction for their scalability and versatility. These methods offer solvent-free, rapid polymerization and reagent-free biofunctionalization, promising large-scale production suitable for clinical translation. The next step in advancing nanoparticle biofunctionalization lies in optimizing biomolecule synthesis, particularly in controlling their orientation for precise interaction with target entities. Such innovations could lead to more customizable, multifunctional nanoparticles, positioning them as powerful tools in diagnostics and drug delivery [13, 14].
Nanoparticles hold significant potential in advancing the global goal of “Good Health and Well-Being” by 2030, transforming medical diagnostics, treatments, and drug delivery. Polymeric nanoparticles (PNPs), known for their biocompatibility and biodegradability, offer unique advantages in overcoming biological barriers. Surface bio-engineering of PNPs by incorporating bioactive elements enables precise control over their interactions at disease sites, which is essential for clinical applications. Recent advancements in the surface functionalization of PNPs for biosensing, bioimaging, drug delivery, and targeted therapeutics were reviewed, evaluating various functionalization methods such as physical, wet chemical, and dry chemical techniques. These methods involve electrostatic, ionic, physisorbed, and covalent interactions that govern the attachment of bioactive molecules to PNPs. Covalent bonding, in particular, enhances the specificity and stability of functionalized PNPs, making them effective for applications like pH sensing, detecting reactive oxygen species (ROS), and identifying biothreats such as viruses and bacteria. The review also highlighted the role of covalent linkages in imaging techniques like computed tomography, magnetic resonance, and optical imaging, ensuring the stability of contrast agents. Physisorption, on the other hand, is crucial for controlled drug release at targeted sites. In vitro and in vivo studies have demonstrated the promising potential of functionalized PNPs in nanomedicine, offering multifunctional solutions for diagnostics and treatments, surpassing the limitations of traditional free agents. Despite ongoing challenges, the surface functionalization of PNPs remains a critical area for advancing targeted therapies and diagnostics.
The authors declare that they have no conflicts of interest.
