Introduction

Nanotechnology is a broad horizon of emerging technologies that can be used to enhance medical treatments. Nanoparticles (NPs) are solid particles or particulate dispersions that contain nanocapsules and nanospheres and are usually produced using polymerization techniques and preformed polymers [1]. Engineered nanoparticles (ENPs) have tremendous potential for increasing disease detection and therapy specificity. Nanomedicine is a multidisciplinary field that encompasses the fusion of biotechnology, nanotechnology, and information technology, resulting in many applications, including drug delivery and in vivo treatments, diagnostic devices, molecular imaging, biomarkers, regenerative medicine, and biosensors, etc. [2]. Nanotechnology offers multiple benefits to overcome the constraints associated with conventional drug administration methods through site-specific and target-oriented conveyances. NPs have shown great potential to enhance the solubility and stability of encapsulated cargos, improve cell uptake, and lengthen circulation duration, which altogether helps increase safety and effectiveness [3, 4]. As a result of these factors, researches on NPs have been widely conducted, yielding encouraging findings in vitro and in vivo (small animal models) [5]. However, delivering a drug to its targeted location is still particularly challenging regardless of these apparent merits.

Recent research showed that only 1% of the intravenously delivered NPs reach their intended target sites [6]. Efforts have been made to increase drug carrier targeting efficiency by attaching cell receptor-targeted ligands to the particle surface [7]. Although this is a significant step forward in achieving targeted drug delivery, the drug carrier must have to overcome various biological obstacles throughout the body to reach the specific target of interest. Even after arriving at their sites of action, prior to the release of their cargo and clearance, NPs must effectively penetrate through the cell membrane and navigate intracellular compartment networks to get to their subcellular mark. Apart from carrier biodistribution, various other impediments require proper overcoming. Despite the comprehensive research prompted by world-renown scientists around the globe, the number of nanomedicines approved by the Food and Drug Administration (FDA) is far less than anticipated, in part due to the translational gaps between animal model species and human trials outcomes, which are not as satisfying as expected [5, 8]. These gaps stem from a persisting lack of knowledge of the physiological and pathological differences between animal models and humans, particularly concerning the mechanisms by which these variations shape nanomedicines' distribution and effectiveness inside the body [9]. Clinical translation of therapeutics is hampered by several factors, of which species differences are not the least ones. Also, patient heterogeneity can hinder nanomedicines' efficacy as currently, only a limited number of clinical trials are available on nanomedicines interactions with stratified patient groups. As a result, only a few nanomedicines are presently suggested as first-line alternative treatments, and many of them only benefit a small proportion of patients [10]. This underappreciated variability in the biological foundations of diseases and across patients partially affects NPs effectiveness by altering the development, shape, and physiology of the pathology-affected tissue.

Considering the vast number of publications and the speed at which data is updated, this study explores the progress and applications of Nanotechnology in the realm of Nanomedicine through a broad, comprehensive overview of the most commonly investigated NPs. Because we expect that Precision Medicine therapies will profoundly affect precision NPs in the near future, we discuss critical biological barriers to targeted therapies involving precision drug delivery and their clinical transition to improve patient-specific therapeutic responses. Additionally, we discuss the challenges and opportunities associated with the most promising and demanding applications of NPs in modern Nanomedicine.

Classes of NPs

Lipid-based NPs

The past decade has witnessed significant attention from scientists toward the Lipid-based NPs (LBNPs), which, due to their biocompatibility, were even considered “nanosafe” carriers. LBNPs present various shapes and sizes, but the most common are vesicle-like spherical platforms made by at least one lipid bilayer surrounding an aqueous interior compartment (Fig. 1). LBNPs can transport large payloads and exhibit various physicochemical properties that can be manipulated to alter their biological features [11]. Such vesicles can upload hydrophobic and hydrophilic pharmaceuticals [12, 13], including vaccines [14], insulin [15], siRNAs [16], proteins [17], and enzymes [18]. They can also be administered intravenously, orally, or transdermally to treat disorders including Alzheimer's disease, cancer, and diabetes [19, 20]. For these reasons, LBNPs are common to most FDA-approved nanomedicines [10, 21].

Fig. 1
figure 1

The diverse types of nanoparticles. Nanoparticles (NPs) could be classified into four main categories according to size, shape, and physicochemical properties. Each class of NPs includes several subclasses, some of which are highlighted here. Each class has numerous advantages and disadvantages regarding conveyed cargo, delivery, and patient responses

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Since liposomes were first characterized by Alec Bangham in 1960, liposomes sparked attention for several decades, most notably when Doxil® was licensed by the FDA and utilized in clinical trials [20]. Liposomes are the largest category of LBNPs, primarily made of phospholipids, and can take on unilamellar or multilamellar vesicular shapes [22]. Liposomes are remarkable drug delivery vehicles as their composition resembles cell membranes. Additionally, they are also biocompatible and biodegradable and can improve drug stability and biodistribution. Generally, NPs stability in vivo and in vitro is mainly affected by their shapes, sizes, surface charges, surface modifications, and preparation methods; these characteristics can be modified during their synthesis [23]. Liposomes are frequently modified (with polymers or ligands) to improve circulation and distribution, making them even more suitable for clinical usage [24, 25]. Several liposome-based biomedical applications are either in clinical trials or soon on the market [26,27,28]. A recent study examined the ability of Pluronic F127 (PF127)- and PEGylated liposomes to penetrate a pathological mucus obtained from chronic obstructive pulmonary disease (COPD). The PEG-liposomes penetrated the mucus barrier effectively after 27 h of incubation [29]. Similarly, nanoscale diagnostic agents can be enclosed within theranostic liposomes for imaging purposes, wherein the therapeutic agent can be encapsulated in the core or incorporated in the lipophilic bilayer shell [30,31,Barriers to delivery faced by systemic administration

The barriers that NPs confront may vary depending on the mode of administration and type and progression of the disease. While local drug delivery approaches allow NPs to overcome some of the barriers associated with systemic drug distribution, they sometimes include more invasive procedures and complex techniques that impose further constraints. Additionally, local delivery may primarily benefit diseases within established and accessible areas of pathology, such as solid malignancies or traumatic injuries. Hence, systemic administration is so far prevalent in NP applications.

Circulation time, structural stability, and clearance in vivo

While in circulation, NPs stability and distribution can be reduced by various factors such as blood flow, excretion, coronas, and phagocytic cells. The physicochemical features of the NP platform determine the precise effects of each of these factors (Fig. 2). This has led to formulating general design concepts to manipulate such parameters to obtain desirable outcomes. For example, NPs with a diameter smaller than 10 nm were demonstrated to be promptly excreted through the kidneys, while if not appropriately designed, NPs with a diameter greater than 200 nm risk activating the complement system [89]. Additionally, several NP formulations use PEGs as a stealth coating to minimize immediate excretion (Fig. 2). PEGylation prolongs the NPs circulation time by altering their size and solubility while protecting the NPs surface from enzymes and antibodies that could cause degradation, secretion, and rapid clearance. Various conjugation strategies were discussed by Veronese et al., along with the critical parameters of PEG structure and molecular weight (MW) required to achieve optimal efficacy of PEG-conjugated drugs [90, 91]. However, this physical barrier does not totally prevent macrophages or other immune system cells from recognizing PEGylated NPs. Furthermore, sometimes PEGylation can induce the development of anti-PEG antibodies, which might result in the rapid elimination of PEGylated NPs, when present in excess concentrations [92]. Clinical investigations have also demonstrated that these anti-PEG antibodies may be detected in individuals who have been exposed to PEG in ways other than through PEGylated medications, suggesting that even the first administered dose of PEGylated NPs may not circulate for an extended period of time in all patients [93].

Fig. 2
figure 2

Illustration of various strategies used to develop smart nanoparticles for precision drug delivery. Material and surface properties, architecture, and targeting responsiveness are characteristics of nanoparticles (NPs) that could be intelligently modified to customize the platform for a particular application. Altogether combinations of these characteristics result in an almost infinite number of NPs features and platforms

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Surface modification approaches enable NPs to circumvent the recognition and clearance mechanisms that might otherwise result in rapid instability and degradation. Various NP design strategies that focus primarily on stability can overcome such issues. NPs stability strongly depends on how their components interact within the environment, as lipid- and polymer-based NPs are particularly prone to unstable and aggregate during circulation and storage. Thus, to increase the stability of these softer NPs, excipients including cholesterol, helper lipids, and PEGylated lipids [23] can be incorporated in LBNPs, whereas cross-linking techniques are apt for polymer-based NPs [94, 95]. Many NPs are lyophilized for storage and transportation to increase their stability. However, this strategy does not alter the stability of NPs once administered [96]. NPs rely on a delicate balance between stability and degradation to effectively release the drug they convey, and this balance must be taken into consideration while designing the NPs. For example, the use of chitosan NPs in nanomedicine, biomedical engineering, as well as the development of novel therapeutic drug release systems with increased bioavailability, sensitivity, and specificity, has increased rapidly in recent years. In addition, chitosan stability is an important factor for its consideration in pharmaceuticals applications. Chitosan-based NPs are usually stable at neutral pH and low temperatures (2–8 ºC). However, at a slighty acidic pH or high temperature (37–50 ºC), NPs start to degrade and release the drug [97, 98]. Similarly, Poly(N-isopropylacrylamide) (PNIPAAm) is a thermo-sensitive polymer. PNIPAAm exhibits a reversible thermo-responsive phase transition at a lower critical solution temperature (LCST). PNIPAAm-coated NPs are stable below the LCST; however, if the temperature exceeds the specific LCST, NPs will start to degrade and release the drug [99, 100]. Once administered, NPs have to encounter varying flow rates in the bloodstream, resulting in shear stress, potentially damaging for the platforms or their payloads, and inhibiting NPs extravasation [101]. These fluid pressures can strip NPs of their surface coatings and prevent them from localizing to vessel walls [101, 102]. Larger micro-particles are more likely to adhere to vessel walls, while non-spherical particles marginate better [102]. Even after vascular localization, architecture-dependent drag forces caused by blood flow may rip NPs from endothelial cell membranes if the NPs lack an adequate binding affinity for the latter [103]. As a result, in vascular pathologies, the frequently altered hemodynamics (due to stenosis and hypertension) experienced by systemically administered NPs significantly impact NPs distribution and delivery [104, 105].

The physicochemical properties of NPs can affect their clearance from the circulation, although the interactions with the reticuloendothelial system (RES) or mononuclear phagocytic system (MPS) are more common events. Phagocytes (primarily macrophages), monocytes, and dendritic cells are involved in RES and MPS, taking up NPs and depositing them in the spleen and liver [106, 107]. This clearance occurs more rapidly in the case of rigid or stiff NPs. In general, cationic NPs are the earliest to be cleared [108], followed by anionic NPs, while slightly negative and neutral NPs have the most prolonged circulation half-lives.

Surface charge plays a significant role in determining cellular uptake efficiency and mechanism, as well as the in vivo fate of NPs [109,110,106, 120]. Receptor-mediated transcytosis is an efficient method of delivering drugs into the brain or infiltrating tumor tissues [121, 149, 150]. Mucus can also trap items via non-specific interactions, allowing their fast removal from epithelial surfaces. Mucus behaves differently depending upon its physiological location due to changes in its composition, hydration, and viscoelasticity [151, 152]. The gastrointestinal mucus forms a thick adhering layer, but the pulmonary mucus is reportedly thinner and more mobile, making it a heterogeneous barrier and preventing drugs from reaching the lungs [151, 152].

Although the mucus behavior is consistent throughout various physiological contexts, mucus features can vary between distinct regions of an organ system, and all these barriers are adaptive. As an example, mucus thickness and turnover rate in the gastrointestinal tract are affected by fiber intake [151, 152]. A significant pH difference exists between the near-neutral ECs surfaces and the acidic intestinal lumen, making the mucosal barrier a destabilizing environment for NP platforms [88, 152]. The pathology of the gastrointestinal system can alter glycosylation patterns, pH, and mucus layer thickness [153]. Similarly, lung diseases do alter local mucus behavior. Mucus in the lungs significantly affects the absorption of inhaled NPs conveying substantial amounts of MUC5AC and MUC5B polymers [154, 155]. However, elevated MUC5B levels and excessive polymer cross-linking reduced mucus pores size and clearance rates in cystic fibrosis, promoting bacterial growth by entrap** pathogens and restricting neutrophil movement [155, 156]. Mucus attributes vary widely depending on patient characteristics, including ongoing pathology, diet, and lifestyle in the respiratory tree, making it a challenging physiological environment for inhaled NPs delivery. COPD is characterized by a thick layer of mucus, needing a novel method for therapeutic drug delivery, i.e., NPs with mucus-penetrating capabilities. In a recent study, Li et al. demonstrated the drug release from nanovehicles by black phosphorus quantum dots (BPQDs) for efficient therapy of COPD. The PEGylated chitosan (CS) nanospheres were coupled with BPQDs. The hydrophilic PEG and the positive charges of CS enabled the nano-vehicles to deeply penetrate the mucus layer (Fig. 4) [85]. Next, the interior of the BPQDs rapidly degraded into nontoxic PO4 and acidic H+, facilitating the dissociation of the PEGylated CS nanospheres and eventually promoting the drug's release [85].

Fig. 4
figure 4

Reproduced with permission from Ref. [85] Copyright 2020, John Wiley and Sons

PEG surface modification enhances the ability of BPQDs to penetrate the sputum layer. A Visual inspection of how various samples penetrate through the artificial mucus layers. B Absorbance (at 595 nm) detection at the bottom layer agarose gel of sputum layer penetration by diverse nanoparticles two h after administration. CS chitosan, AM amikacin, BPQDs black phosphorus quantum dots.

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Cellular uptake and intracellular trafficking barriers

Even once NPs have contacted target cells, several barriers to NPs absorption and intracellular trafficking influence their functional cargo delivery (Fig. 3). This section discusses the barriers a nanocarrier must overcome in order to achieve a proper cellular uptake and internal trafficking. The intracellular barrier is the final biological hurdle against the delivery of therapeutic agents. The corona, combined with altered NP properties, including hydrophilicity and charge, affects cellular absorption in macrophages, cancer cells, and numerous other cell types [157, 158]. Cell surfaces are composed of negatively charged phospholipid bilayers that hold biomolecules in a fluid mosaic structure [157, 159]. Human cells have around 400 types of cell surface transporters, with lipid rafts and transmembrane proteins being the most common membrane components [157, 159]. Additionally, the precise rigidity of the cell membrane and its structural fluidity is partly regulated by the cytoskeleton, which dynamically responds to external inputs [160].

Thus, NPs engaging with the same cell type may have distinct interactions based on their cell membrane locations and/or contact time. Due to reciprocally repulsive negative charges, anionic NPs struggle to engage the cell surface. Conversely, cationic NPs with excess positive charges can damage the cell membrane and induce cytotoxic effects [161, 162]. Thus, the first encounter between an NP and a cell may decide the NP's fate and therapeutic potential. Few definite trends about the optimized NPs shape and size have been established regarding cellular uptake. According to several studies and models, spherical NPs outperform rod-shaped NPs in non-phagocytic cells [163], while other studies demonstrate the reverse upshot [164, 171]. Thus, both phenotypes and cell types contribute to the heterogeneity of the cell population, posing a variety of challenges to NP delivery. However, recent advances in NP design may help overcome these constraints.

Alternative strategies to enhance nanoparticle design

To account for the significant variability of disease states and biological barriers within and between patient groups, strategies for administering therapeutics must be exceedingly modular and adaptable. Nanomedicine and nanodelivery systems can be produced in various ways, which may lead to a greater scientific understanding of their in vivo interactions, facilitate clinical translation, and enable the development of novel therapeutic approaches. The differences in NPs composition and structure make it challenging to predict and control off-site ancillary effects. The latter include inflammation, undesired organ targeting, and sequestration by the MPS. This section discusses the impacts on the delivery of various NP characteristics, emphasizing how specific choices about NP design can overcome barriers tailored to particular diseases.

Rapid degradation and elimination strategies

A significant barrier to NPs is the drastically distinct metabolic pathways that differentiate them from small-molecule drugs or biologicals. While the pharmacokinetics of these common/conventional medications have been thoroughly studied and proven, NPs often show different behaviors for reasons rooted in their macromolecular structure. Simultaneously, the bulk of smaller organic molecules is removed predictably and efficiently through various metabolic pathways. Conversely, numerous nanomaterials defy rapid and effective clearance from the body. Human biology lacks the metabolic pathways or mechanisms capable of processing significant quantities of nanomaterials or nanoscale particles. Additionally, the proclivity of many NPs to target specific organs, particularly the liver and spleen, enhances the possibility of triggering (potentially deleterious) secondary effects, especially when, after administration, bio-persistent materials loiter for long and possibly cause off-site ancillary effects [172].

Constructing the NP delivery systems from biodegradable nanomaterials is a workable and practical strategy apt for mitigating the secondary impacts of biopersistence. Under physiological settings, biodegradable nanomaterials break down into nontoxic compounds, and their elimination via natural pathways is rapid. For instance, PLGA is a copolymer of polylactic acid and polyglycolic acid that degrades into its two original monomers, lactic acid, and glycolic acid, which are two naturally occurring metabolites in human physiology. Consequently, biodegradable nanomaterials, such as polylactic acid, poly(amidoamine), and chitosan, are widely used [173]. These polymer systems are highly adaptive and versatile and can modulate a condition-specific degradation, such as pH, or systematically regulate their own degradation rate. In vivo, biodegradable NPs used in medical applications are more likely to disintegrate in bursts rather than gradually decay [172]. Even though an NP is biodegradable, its physicochemical features, such as charge, size, and hydrophobicity, may exert undesirable effects on the blood coagulation system. An alternate approach to ease the removal of intravenously delivered NPs is synthesizing ultrasmall (~ 10 nm) NPs with positive surface charges [174]. Ultrasmall NPs filtration by the renal glomeruli and urinary excretion is swift. This approach was clinically tested: inorganic silica-coated C-dots with a diameter of approximately 7 nm were quickly cleared by the kidneys [175, 176]. A disadvantage of ultrasmall particles is that their extremely quick elimination may not suit specific nanomedicines. However, an improvement of this method might be using biodegradable NPs, such as bigger polymeric NPs, that dissolve or dissociate into smaller components the kidneys can clear.

Harnessing the Corona Towards Nanoparticle Design

The "corona" is a critical factor regulating NPs interactions with the host's biology. Historically, the corona development has been considered as an undesired 'biofouling' that should be prevented, for example, by using low-adhesion NP coatings, such as PEG or other 'stealth' materials, to obscure the particle from immune detection and reduce its biological interactions. However, it is unlikely that the corona formation, which affects the NPs biological outcome, will ever be fully eliminated. A more forward-thinking approach to nanotherapeutics would be promising strategies that may result in a better scientific knowledge of NPs interactions in vivo to develop innovative treatments. The corona should be viewed as an NP's extension rather than an obstacle. Its development and composition should be studied and analyzed, considering the particle's intended purpose. One may use the NP's immaculate identity as a foundation to construct its biological profile. Thus, altering the corona architecture can alleviate issues associated with nanotherapeutics, including biodistribution, cytotoxicity, immunogenicity, and intracellular compartmentalization. In order to enhance the in vivo biological behavior, NP surfaces are modified with chemical agents or coated with various proteins and lipids [79, 177, 178]. It is possible to control the NP's biomedical behavior by controlling material parameters. Corona preformation is a simple practice by which, before their administration, NPs are preincubated ex vivo in a predetermined medium with the desired corona components. Corona preformation enables some degree of control over the corona makeup and can be applied to all the currently available NP types. Although this technique was studied in animal models primarily using albumin as the sole corona constituent, this unsophisticated and rather simple method has demonstrated its potential to reduce the binding of opsonin and complement immune factors while improving NPs stability and decreasing particle cytotoxicity [179, 180]. More sophisticated preconfigured coronas can be developed with a greater understanding of nano-bio interactions, such as easing NPs targeting or reducing off-target ancillary effects associated with NP biopathology. However, since the NP's corona is a dynamic shell [181], this approach has limitations and drawbacks. Although a preformed corona may play a role in deciding an NP's first biological identity, it is a temporary structure susceptible to altering the host's biological environment.

Another more sophisticated and advanced method to harness the corona is to use an in-silico modeling technique for rational particle design, allowing to forecast and direct corona development in vivo. The software modeling molecular dynamics and structure–activity relationships could predict corona assembly and NP-cell interactions [182, 183]. More modeling could analyze how corona-bearing NPs interact with biological barriers and their behavior in biological systems. These approaches could be combined into a rational particle design. The NP's physicochemical properties, shape, and functionalization should be devised to enable the assembly of a corona of the desired composition, i.e., suitable for the NP's biological function.

Similarly, related research showed that manipulating the polysaccharide chain structure outside a dextran NP can activate certain complement immune pathways [184]. The NP surface can be functionalized to attract specific components into the corona. Thus, an AuNPs functionalization motif was designed in silico to include transferrin from blood serum into the corona. Additionally, a recent study of NP surface chemistry showed that it is possible to influence the conformation of the bound corona components. In fact, polymeric NPs endowed with distinct surface functional groups could stabilize or denature the corona's proteinaceous albumin [185].

Altogether, these investigations have revealed that it is possible to 'fine tune' the NP's corona to minimize undesirable off-site ancillary effects. However, none of these experimental methodologies is exhaustive. Hence, a combination of diverse analytical approaches is needed to predict the in vivo biological outcomes and the practical application of the coronas in pharmaceutical sciences. Such as, it is necessary to perform a thorough assessment of the NP-protein interaction under-stimulated biomimetic conditions [186, 187]. It is especially critical to carefully set up media exposure factors such as proteins, fluidic shear stress, and degradable enzymes. Furthermore, new pharmaceutical technologies like tumor-on-a-chip models and biomimetic microfluidic systems allow for a deeper examination of NP behavior [188]. However, the practical barriers and insufficient information about the nano-bio interface should be addressed. To be effective, both the preformed corona method and the rational NP design strategy require a much deeper understanding of corona dynamics and biological interactions.

Advanced biocompatible and biomimetic NPs

A particle's biocompatibility corresponds to its potential to avoid causing unpleasant reactions in the host biology, as many of such adverse reactions are products of undesirable interactions with nanomaterials. Obviously, any clinical application requires a high degree of biocompatibility. However, NPs materials of frequent clinical use, such as PEGylated NPs, may be less biocompatible than previously assumed. Many investigations have discovered a significant incidence of anti-PEG antibodies in patient sera [93, 189], showing that PEGylation is relatively immunogenic. As a result, we must perfect and enhance currently available nanomaterials. Fundamental elements of pristine identity, including physicochemical properties, shape, geometry, and density, significantly affect NPs biocompatibility and thus should be tailored to meet different requirements and help modulate the Nano-Bio interactions. For example, it is known that deformable disc-shaped and hemispherical polymeric particles outperform rigid and spherical particles in terms of biocompatibility, possibly because they mimic the shape, size, elasticity, and surface tension proper of erythrocytes [190].

Apart from employing synthetic nanomaterials, another strategy for improving biocompatibility is incorporating biomaterials into the NP design. This approach could be beneficial by mitigating adverse off-site ancillary effects associated with NPs, as endogenous materials are far less likely to elicit unpleasant reactions. The NP can be masked with a biomimetic exterior by cloaking it in native material using natural biomolecules.

Another method is to conjugate the NPs surface to cell membrane/platelet-derived vesicles, or even to whole cells, to effectively 'hitchhike' the NPs and conceal them via the associated cell membrane, as is the case of the NPs conjugated with erythrocytes [191, 192]. However, this approach might trigger unintended NP-induced effects on the carrier erythrocytes and thus requires the refinement of NPs [193]. Encapsulating the NPs into cell-membrane-derived microvesicles generated from the host's own collected cells is another innovative variation of this approach [218]. However, these platforms have enormous potential for improving the efficacy of precision medicine therapies. Potential future applications of metal-based NPs such as gold, silver, and magnetic NPs in diagnosis and therapy could advance the development and use of nanomedicines on a larger scale. For example, AuNPs have garnered a lot of attention, as they appear to be readily absorbed by soft tumor tissues and render the tumor more susceptible to radiation (e.g., in the near-infrared)-based heat therapy for selective elimination [219, 220]. Most of these materials are biocompatible and stable, and they fulfill specialized applications that need qualities that organic materials cannot provide. However, there is a need for continuous innovation, and currently, the technology is in the infancy stage of research. In addition, scientists and researchers should also emphasize the immune response in living organisms rather than concentrating solely on develo** nanomaterials that have similar structures to native tissues.

Besides, restricting the number of patients eligible for specific NP-based therapeutics might reduce the potential market size. At the same time, the cost of NP-based therapeutics could be high if only a specific population group could administer them. However, NP platforms that are effective in certain patient populations may have the potential to administer various precision-based and generic therapeutics. Thus, constructing a single NP platform effective for a stratified population might result in several successful therapeutic applications. Moreover, precision NP designs may allow for better therapeutic efficacy than NPs produced for wide populations, and considerable gains in survival, quality of life, and even dosage might justify the increased cost of these precision delivery systems.

Conclusions

This review has explored several conceptual NP engineering designs for the successful administration of therapeutics and their tailoring to overcome the various biological barriers met across patients suffering from diverse diseases. Such barriers to proper drug delivery are worsened by patients' comorbidities, disease development phases, and specific tissues physiology. NP platforms can be customized in terms of shape, size, charge, and surface qualities to maximize delivery for a particular application, treatment, and patient group. These NP features have been researched across several biological conditions, and in certain situations, exploitable trends have been validated for intelligent NP design. For instance, the charge is crucial to muco-penetrating NPs and intracellular applications that need an escape from endosomes. Applications requiring cell types to absorb NPs gain precedence over-targeting surface markers, such as in many cancers and therapeutic applications. These breakthroughs in NP design entail enormous potential to increase the effectiveness of Precision Medicine therapies, but diagnostic applications have yet to see clinical developments. This lack of clinical advancements is mainly due to evaluating the efficacy of NP platforms in large populations. The considerable variability in biological barriers found in high numbers of patients may obscure the possibility of successfully treating smaller subgroups. Thus, further explorations into NPs design and later interactions inside the human body are necessary to increase the precision of these claims, particularly as we move toward stratifying patient populations to set up the most proper NP platforms for each subgroup.