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or higher size range[32]. Toxicity in biological systems generated by NPs is predominantly through the formation of oxidative responses and consequent formation of free radicals. Free radicals are hazardous as they oxidize the lipid and damage the DNA with inflammatory responses. The data also shows that the smaller the size, the more able it is toward the formation of reactive oxygen species [20]. Every NP thus closely needs to be monitored for its new developed chemical reactivity, and it should be done from its development phase.

      2.2.1.3 Surface

The surface of NMs is a unique property, and the surface phenomenon seems to be a new direction in developing nontoxic NPs. The groups present on the surface or coating can change the physical, chemical, magnetic, electrical, and optical properties of NPs, which invariably can alter in vivo solubility, partition coefficient, distribution, pharmacokinetics, and accumulation [32–34]. The presence of oxygen on the surface can lead to the generation of reactive oxygen species that may lead to toxicity [24, 35]. In pharmaceuticals, the effect of NPs based on conformation has always been of interest for the formulation developer. The endocytic system in the body can actively remove any nanosize foreign material from the body, and same observed with drug loaded NP and cannot perform their desire role. The reason could be negatively charged cell membrane. Against such cell membrane, positive, negative, or neutral charge NPs cannot behave in the same manner. Similarly, NPs with lipophilic surface will have more affinity and eventually be quickly absorbed through the lipid bilayer membrane of the cell, while NPs coated with hydrophilic polymers such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and dextran avoid interaction due to the hydrophobic cell surface [16]. The surface energy of NPs alters the capacity to diffuse through the blood–brain barrier. The data shows that the anionic energy on the surface of NPs with the size range of 50–500 nm is transported through all layers of the skin, in contrast to the neutral or cationic NPs that do not have such similar characteristics [20].

      2.2.1.4 Shape

      The study has shown that the membrane diffusion of NMs is deviated based on its surface structure design. Yet, the type of surface of the NMs and their relationship with membrane diffusion are far from being broadly understood [36, 37]. Classically, interactions between NMs and the tissues of living things are driven by the chemical functionalities on the surface in addition to their shape and size. The importance of the surface can also be enlightened from a well‐known phenomenon of naturally occurring peptides that show the inability to perform their fate of getting diffused into the cell membrane if they remain in random coil configuration rather than specific helical structure [36]. Different shapes, viz., fiber, spheres, tubes, ring, and planes, have been assessed to achieve their potential characteristics, including their adverse effects. Nickel NPs used in electronic application while testing toxicity based on size demonstrated that the change in configuration has more toxicity rather than the size [37]. The data shows that endocytosis of globular particle is quicker when compared to cylinder‐shaped particles in nanoscale [38]; further toxicity of globular NPs is based on whether their configuration is homogenous or heterogeneous [39], and if they are other than spherical, then they will quickly show movement in systemic circulation, with possible biological consequences [40].

      2.2.1.5 Composition and Crystalline Structure

      For the preparation of NMs, various metals, polymeric materials, and bioceramics have been used. For medical purpose, phospholipids, PEG, and natural polymers have been used for formulation. It is the phospholipid that makes NMs compatible with the human tissue as the cell walls are made up of the same phospholipid. The composition of ethosomes has made it possible for them to enter through the skin from the space smaller than their own diameter by deforming the structure. One important report on the effect of composition of NPs on few species having vital role in trophic levels showed that the nanosilver and nanocopper with their soluble forms caused toxicity in all tested organisms, whereas TiO₂ of the same dimensions did not cause any toxicity issues [41]. Crystal form of NPs also influences the toxicity, and it has been reported that crystalline TiO₂NPs show toxicity in the absence of light including oxidative DNA injury, whereas NPs of metastable form of the same material with the same size and chemical composition do not show such toxicity [25]. In one more report, the cytotoxicity was previously claimed due to the size and then due to ultrahigh reactivity of NMs itself [42]. Several such materials of composition, viz., metals, aluminum oxide, gold, copper oxide, silver, zinc oxide, iron oxide, and titanium oxide; nonmetals, such as carbon and silica; and polymeric materials, have shown toxicity not only in animals and humans but also in nature [43].

      2.2.2 Large‐Scale Manufacturing of Sustainable Nanomaterials

      The cutting‐edge technological applications and characteristic advantage of NMs are due to their physical properties, composition, and colloidal stability (if in liquid form), and at the same time these factors are vulnerable from the view point of environment and health; so, henceforth, sustainable processes for the large‐scale productions are desirable. The situation is that the scaling up of NPs/NMs on large scale, despite tuning nanoscale features, has become a technological barrier for the development. Apart from scale‐up, concerns are raised for the toxic manifestations of NMs through their varied mechanisms for both environmental and health issues, although no clinically pertinent toxicity with their mechanism has yet been established that can prove them hazardous over their expediency. Sometimes, the methods of detection of toxicity and models used for the same are conflicting and inconsistent. So, based on few experimental models, judging more valuable NPs as more toxic to biological systems or vice versa is inappropriate [43].

      Large‐scale manufacturing aims for superiority, desired nanoproduct stipulations, desired physicochemical constraints, and sterility requirements. For such mass production of NMs, the selection of methods depends on the following factors:

      1 Type of approach used;

      2 type of NMs; and

      3 regulatory requirements for production.

      2.2.2.1 Type of Approach

Broadly, the tuning of particle size for nanoscale is being carried out by two approaches: top‐down (TD) and bottom‐up (BU). In TD approach, there is diminution of larger materials into smallest possible size, while in the BU approach there is assembly, aggregation, or formation of NPs, atom by atom, through precipitation or growth of nuclei. In TD method, pulverization can be achieved by means of impact (such as hammer mill) and attrition alone or impact and attrition (ball mill and fluid energy mill) together. This approach requires high energy requirement and fewer steps. The main issue with such impact‐ and/or attrition‐based mill is unavailability of narrow size range. Still narrow size range can be achieved, but that will bring huge amount of waste.

      BU approach is well known for its customization in design such that it reduces waste production, but this method uses organic solvents. Even after completion of the manufacturing process, these organic solvents remain in the system and need additional step for their removal, and thus, toxicity of residual solvents always remains a threat in NMs manufactured by such methods.

      The use of organic solvents can be replaced with few nonorganic solvents. Such green methods use supercritical fluids (supercritical CO₂, ethyl alcohol, or water) that bring extremely pure NMs. The greener methods require exclusive pressurized apparatus with further successive steps [44]. Green methods for the production of NMs can address sustainability issues scalable for large manufacturing, cost‐effective, versatile, and tunable nonagglomerated nanoclusters and overcome the key barrier for the progress of large‐scale manufacturing of NMs.

      2.2.2.2 Types of Nanomaterials

      The essentiality of a sustainable approach to nanotechnology is becoming more and more urgent in the past few decades while many questions concerning all the steps of nanomanufacturing are unanswered [45]. Apart from issues concerning scale‐up and large‐scale manufacturing, materials‐related issues need to be addressed that are selected based on the type of NMs being

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