The toxicological profiles of nanoparticles are significantly influenced by their surface characteristics, with functionalized nanoparticles often exhibiting distinct biological behaviors compared to their bare counterparts. Surface modifications such as PEGylation or chitosan coatings alter interactions with biological systems, affecting cellular uptake, biodistribution, and clearance. Understanding these differences is critical for designing safer and more effective nanomaterial-based applications, particularly in biomedical fields.

Bare nanoparticles, lacking surface modifications, often exhibit high surface energy and reactivity, leading to aggregation in biological environments. This aggregation can enhance nonspecific protein adsorption, forming a protein corona that influences cellular interactions. The protein corona may mask the nanoparticle's original surface properties, leading to unpredictable biodistribution and increased recognition by the immune system. For example, bare metal oxide nanoparticles like TiO2 or ZnO can induce oxidative stress and inflammation due to their reactive surfaces, which catalyze free radical generation. Similarly, bare quantum dots containing cadmium or other heavy metals may leach toxic ions, causing cytotoxicity and long-term accumulation in tissues.

PEGylation, the covalent attachment of polyethylene glycol (PEG) chains to nanoparticle surfaces, is a widely used strategy to improve biocompatibility. PEGylated nanoparticles exhibit reduced protein adsorption, minimizing opsonization and subsequent clearance by the mononuclear phagocyte system. This stealth effect prolongs circulation time, making PEGylation advantageous for drug delivery applications. Studies have shown that PEGylated gold nanoparticles exhibit significantly lower hepatic and splenic accumulation compared to bare counterparts, with circulation half-lives extended by several hours. However, the molecular weight and density of PEG chains influence toxicological outcomes. Low-density or short-chain PEG coatings may fail to prevent protein adsorption, while excessive PEGylation can hinder cellular internalization, reducing therapeutic efficacy. Additionally, repeated administration of PEGylated nanoparticles has been linked to accelerated blood clearance due to anti-PEG antibody production, raising concerns for chronic use.

Chitosan-coated nanoparticles present another functionalization approach, leveraging the biocompatibility and mucoadhesive properties of chitosan, a polysaccharide derived from chitin. Unlike PEGylation, chitosan coatings promote cellular uptake, particularly in mucosal tissues, making them suitable for oral or pulmonary delivery. The positive charge of chitosan at physiological pH facilitates interaction with negatively charged cell membranes, enhancing endocytosis. For instance, chitosan-functionalized silica nanoparticles demonstrate higher epithelial uptake compared to bare silica nanoparticles, with reduced cytotoxicity due to diminished direct contact between the nanoparticle core and cellular components. However, the degree of deacetylation and molecular weight of chitosan influence toxicity profiles. High-molecular-weight chitosan may induce greater inflammatory responses, while low-molecular-weight variants can exhibit better tolerability but reduced adhesion efficiency.

Cellular uptake mechanisms differ markedly between bare and functionalized nanoparticles. Bare nanoparticles often enter cells via passive diffusion or nonspecific endocytosis, leading to heterogeneous intracellular distribution and potential lysosomal degradation. In contrast, PEGylated nanoparticles rely more on active transport pathways, with reduced uptake rates due to their stealth properties. Chitosan-coated nanoparticles exploit charge-mediated interactions, often resulting in clathrin- or caveolae-dependent endocytosis. These differences in uptake pathways influence subcellular localization and subsequent toxicity. For example, bare silver nanoparticles accumulate in lysosomes, inducing lysosomal membrane permeabilization and apoptosis, whereas PEGylated silver nanoparticles show reduced lysosomal uptake, mitigating cytotoxicity but potentially limiting antimicrobial efficacy.

Clearance pathways also diverge between surface-functionalized and bare nanoparticles. Bare nanoparticles are rapidly opsonized and cleared by the reticuloendothelial system, primarily accumulating in the liver and spleen. This rapid clearance can lead to acute toxicity in these organs. PEGylation redirects nanoparticles toward renal excretion, provided their hydrodynamic diameter remains below the renal filtration threshold. Chitosan-coated nanoparticles, depending on their size and charge, may undergo hepatic clearance or mucociliary expulsion in pulmonary applications. The biodegradability of chitosan further allows enzymatic breakdown, reducing long-term accumulation risks compared to synthetic polymers like PEG.

Immunotoxicity represents another critical consideration. Bare nanoparticles frequently trigger innate immune responses, activating complement systems or provoking macrophage infiltration. PEGylated nanoparticles generally exhibit lower immunogenicity, though anti-PEG immune responses can develop over time. Chitosan-coated nanoparticles may stimulate mild immune activation due to their polysaccharide nature, which can be advantageous for vaccine adjuvants but problematic for chronic therapies.

In summary, surface functionalization profoundly alters the toxicological profiles of nanoparticles. PEGylation enhances biocompatibility and circulation time but may compromise cellular uptake and induce immune reactions upon repeated dosing. Chitosan coatings improve mucosal adhesion and cellular internalization while maintaining biodegradability, though their charge-dependent interactions require careful optimization. Bare nanoparticles, while simpler to produce, pose higher risks of aggregation, protein corona formation, and uncontrolled biodistribution. The choice of surface modification must align with the intended application, balancing toxicity, efficacy, and clearance requirements. Future research should focus on long-term in vivo studies to fully elucidate the chronic effects of these functionalization strategies.