How Nanoparticle Properties Drive Their Toxicity: A Comprehensive Review

Abstract

Nanoparticle synthesis, characterization, and novel applications are central to contemporary nanotechnology. Engineered, water‑soluble nanoparticles enable breakthroughs in biomedical diagnostics and therapeutics—imaging genetic markers, targeting drug delivery, and enabling photodynamic or hyperthermic cancer therapies. Yet, the inherent toxicity of many nanoparticles remains a critical barrier to clinical translation. Current research probes the cellular and organismal effects of nanoparticles through in vitro assays and in vivo animal studies, aiming to link specific physical and chemical attributes to observed toxic mechanisms. This review consolidates the latest evidence on how nanoparticle size, shape, surface charge, composition, and shell chemistry govern their biological interactions and adverse outcomes.

Background

The International Organization for Standardization defines nanoparticles (NPs) as structures with at least one dimension between 1 – 100 nm. Beyond size, NPs differ in electrical charge, core or shell composition, geometry (tubes, rods, films), and origin (natural vs. engineered). While their utility spans electronics, agriculture, textiles, and medicine, toxicity to living organisms is the primary constraint on their therapeutic and diagnostic deployment. Researchers must balance therapeutic benefits against potential side‑effects, choosing appropriate in vitro (cell lines) or in vivo (animal) models to capture the full spectrum of interactions—from cellular uptake to organ‑wide distribution. A nuanced understanding of how concentration, exposure duration, biological fluid stability, and tissue accumulation influence toxicity is essential for designing safe, biocompatible nanoparticles.

Medical Applications of Nanoparticles

In clinical settings, NPs serve as fluorescent labels, contrast agents, drug carriers, and agents for photodynamic or hyperthermic tumor ablation. Gold nanoparticles (AuNPs) are already employed for drug delivery and tumor imaging due to their high biocompatibility, although long‑term toxicity data remain incomplete. Micellar, liposomal, and polymer‑based NPs, as well as single‑ and multi‑walled carbon nanotubes, provide versatile platforms for targeted therapy, reducing the systemic dose required and thereby mitigating potential toxicity.

Quantum dots (QDs) and superparamagnetic iron‑oxide NPs offer powerful imaging capabilities across visible, infrared, and magnetic resonance modalities. Carbon‑nanotube‑based biosensors have advanced glucose monitoring, DNA detection, and bacterial identification. Silver nanoparticles (AgNPs) are prized for antimicrobial activity in wound dressings, implants, and cosmetics. Nevertheless, the unique physicochemical attributes that enable these functions can also drive toxic responses in biological systems.

Mechanisms of Nanoparticle Toxicity

Nanoparticle toxicity is governed by size, shape, surface area, charge, catalytic activity, and the presence or absence of surface coatings. Their nanoscale dimensions facilitate penetration through epithelial and endothelial barriers, enabling systemic distribution to the brain, heart, liver, kidneys, spleen, bone marrow, and nervous system. Nanoparticles can traverse cell membranes via endocytosis or passive diffusion, and can even infiltrate organelles such as mitochondria and nuclei, disrupting cellular metabolism and DNA integrity.

Key toxic pathways include:

1. Generation of reactive oxygen species (ROS) leading to oxidative stress.
2. Membrane perforation and physical disruption.
3. Interference with cytoskeletal dynamics.
4. DNA damage and transcriptional dysregulation.
5. Mitochondrial dysfunction and energy imbalance.
6. Impairment of lysosomal degradation and autophagy.
7. Alteration of membrane protein function and transport.
8. Induction of inflammatory mediators.

For example, cadmium‑based QDs release Cd²⁺ ions upon oxidation, triggering ROS production and mitochondrial injury. TiO₂ nanoparticles with a rutile crystal structure cause DNA strand breaks, whereas anatase‑structured TiO₂ is largely non‑toxic. Nanoparticles of 50 nm can perforate alveolar cell membranes, resulting in necrosis, while smaller particles may preferentially localize to the nucleus and interfere with transcription.

Relationships of Nanoparticle Toxicity with Their Physical and Chemical Properties

Extensive meta‑analysis of 307 studies (1,741 data points) on CdSe quantum dots revealed that surface chemistry, diameter, assay type, and exposure time collectively predict cytotoxicity, underscoring the need to tailor each attribute to the intended application.

Size

Nanoparticles exhibit a high specific surface area, enabling strong interaction with biomolecules. Size dictates cellular uptake routes: particles < 5 nm cross membranes non‑specifically, whereas 10–25 nm particles are internalized by pinocytosis. AuNPs ≤ 6 nm enter the nucleus; 10–16 nm particles remain cytoplasmic. Smaller NPs (≈ 1.4 nm) are 60‑fold more toxic than 15 nm counterparts and can trigger apoptosis or necrosis within 12 h, likely due to their ability to fit into DNA major grooves and obstruct transcription.

Shape

Shape influences endocytosis and cellular penetration. Spherical NPs are internalized more readily than nanotubes, while needle‑like hydroxyapatite particles cause higher cell death than spherical forms. Graphene oxide nanosheets physically damage membranes; protein adsorption mitigates this effect. Shape also determines tissue‑specific accumulation—for instance, star‑shaped gold NPs preferentially localize in lung tissue.

Chemical Composition and Crystal Structure

Core composition dictates metal‑ion leakage. ZnO NPs induce oxidative stress; SiO₂ NPs disrupt DNA. Surface coatings (polymer, silica, gold shells) can suppress ion release and enhance stability. Crystal lattice matters: rutile TiO₂ causes oxidative DNA damage; anatase TiO₂ is benign. Environmental conditions can alter crystal structure, influencing toxicity.

Surface Charge

Positively charged NPs exhibit higher cellular uptake and toxicity due to electrostatic attraction to negatively charged membranes and DNA. Negatively charged particles are less internalized but may preferentially accumulate in tumor cells when conjugated with targeting ligands. Protein coronas formed in biological fluids can mask surface charge, alter aggregation, and influence biodistribution.

Shell and Surface Modification

Coatings enhance solubility, reduce aggregation, and shield the core from biological environments, thereby diminishing toxicity. For example, PEGylation improves circulation time and reduces opsonization, while functional shells (e.g., lectins) enable selective tumor targeting. Quantum dot shells (ZnS, SiO₂) prevent heavy‑metal ion release, decreasing genotoxic risk.

Study of Nanoparticle Toxicity

Nanotoxicology integrates in vitro and in vivo approaches. Cell‑culture models reveal molecular mechanisms, while animal studies assess systemic effects and delayed toxicity. Co‑culture and 3‑D models bridge the gap between simplified monolayers and whole‑organ responses, offering more predictive insights into biodistribution and cellular uptake.

In Vitro Studies

Primary cultures of intestinal, blood, pulmonary, and skin cells are tailored to the anticipated exposure route. Co‑cultures (e.g., Caco‑2 with Raji cells) and 3‑D spheroids mimic tissue architecture, providing data that align more closely with in vivo outcomes.

In Vivo Studies

Animal experiments confirm biodistribution, organ accumulation, and systemic toxicity. TiO₂ NPs injected intravenously at 5 mg/kg showed no adverse effects over 28 days. Silver NPs displayed size‑dependent toxicity, with larger particles inducing less damage. Quantum dots, despite heavy‑metal cores, can be rendered relatively safe via robust shells and protein coronas, though long‑term studies remain limited.

Conclusions

Nanoparticle toxicity is intrinsically linked to their size, shape, charge, composition, and surface chemistry. Designing safer NPs requires systematic optimization of these attributes and rigorous evaluation using relevant in vitro and in vivo models. Continued research into mechanistic pathways will enable predictive toxicology, accelerating the translation of nanomedicines while safeguarding patient health.

Abbreviations

FDA

Food and Drug Administration

IL-1β

Interleukin‑1‑beta

MRT

Magnetic resonance tomography

NP

Nanoparticle

QD

Quantum dot

ROS

Reactive oxygen species

SEM

Scanning electron microscopy

TEM

Transmission electron microscopy

TNFα

Tumor necrosis factor‑alpha