Nature Reviews Drug Discovery2010ReviewDrug Delivery

Strategies in the Design of Nanoparticles for Therapeutic Applications

Robby A. Petros And Joseph M. Desimone29 September 2026DOI 10.1038/nrd2591

Summary

Engineered nanoparticles have shown promise for targeted drug delivery, but first-generation systems (liposomes and polymer–drug conjugates) have not overcome all biological barriers required for effective therapy. Key barriers include opsonisation and RES clearance, inefficient cargo encapsulation and triggered release, poor cellular/subcellular targeting, and heterogeneous tumour microenvironments. The review argues that rational design—based. Size effects: Particles <5 nm are rapidly cleared by renal filtration or extravasation. Rigid spherical particles of 100–200 nm have the highest potential for prolonged circulation. Particles >200 nm are filtered by the.

Keywords

Nanoparticles Polymeric Liposomes Biodistribution Micelles Nanocarriers siRNA

Purpose: Engineered nanoparticles have shown promise for targeted drug delivery, but first-generation systems (liposomes and polymer–drug conjugates) have not overcome all biological barriers required for effective therapy. Key barriers include opsonisation and RES clearance, inefficient cargo encapsulation and triggered release, poor cellular/subcellular targeting, and heterogeneous tumour microenvironments. The review argues that rational design—based on size, shape, surface chemistry, and stimuli-responsive matrix chemistry—is needed to develop next-generation polymer-based nanoparticles.

Hypothesis: As a review article, this work does not test a single hypothesis. Its central thesis is:

If nanoparticle characteristics—size, shape, surface properties, matrix chemistry, and targeting ligands—are rationally engineered, then nanoparticles can overcome systemic, organ-level, cellular, and subcellular biological barriers, leading to improved biodistribution, targeted delivery, and therapeutic efficacy.

Aims: Primary Aim: To review recent progress in the rational design of engineered nanoparticles for therapeutic applications, with emphasis on polymer-based systems. - Secondary Aims: - To discuss the impact of particle size, shape, and surface characteristics on biodistribution, circulation time, and cellular internalisation. - To outline biological barriers at the systemic, organ, cellular, and subcellular levels and strategies to overcome them. - To review targeting strategies: passive (EPR effect), active non-selective (transferrin/folate), and active selective (antibodies, aptamers, peptides). - To highlight stimuli-responsive release mechanisms (reductive, pH-sensitive, enzymatic) and organelle-specific targeting. - To identify remaining challenges and future directions for clinical translation.

Delivery system:

Platform Type: Liposomes; Examples Discussed: Doxil (liposomal doxorubicin), AmBisome, DepoDur; albumin-coated liposomes; RGD-targeted liposomes

Platform Type: Polymer–drug conjugates; Examples Discussed: PEG–L-asparaginase (Oncaspar), PEG–interferon, PEG–G-CSF; HPMA copolymers

Platform Type: Polymeric nanoparticles; Examples Discussed: PRINT particles, filomicelles, dendrimers, polymeric micelles, cyclodextrin-based siRNA nanoparticles

Platform Type: Albumin-based nanoparticles; Examples Discussed: Abraxane (albumin-bound paclitaxel)

Platform Type: Controlled-release implants; Examples Discussed: Zoladex (goserelin), Gliadel (carmustine)

Platform Type: Payloads; Examples Discussed: Doxorubicin, paclitaxel, cisplatin, siRNA, oligonucleotides, imaging agents (e.g., ¹¹¹In), proteins

Platform Type: Targeting Ligands; Examples Discussed: Transferrin, folate, PSMA antibody J591, RGD peptide, nuclear localisation signals, triphenylphosphonium (mitochondria)

Platform Type: Stimuli-Responsive Chemistry; Examples Discussed: Disulphide bonds (reductive), hydrazone linkers (acidic pH), enzymatic cleavage, light/magnetic triggers

Approach: This is a narrative review synthesising literature from the 1950s to 2010. No primary experimental data are presented. The review includes:

A historical timeline of nanoparticle therapeutic development.
Box 1: Early history of nanoparticle therapeutics.
Box 2: Targeting tumour angiogenesis.
Figures illustrating nanoparticle surface modifications, modes of cellular internalisation, PRINT technology, and stimuli-responsive release.
Comparative analysis of design parameters across multiple nanocarrier platforms.

Key methods: As a review, the “methods” are literature synthesis and comparative analysis. Key techniques from cited studies include:

Particle fabrication: PRINT (Particle Replication in Non-wetting Templates), self-assembly, emulsion polymerisation.
Characterisation: SEM, DLS, zeta potential.
Cellular uptake: In vitro internalisation assays (e.g., HeLa cells), phagocytosis assays with alveolar macrophages.
Biodistribution: In vivo circulation half-life studies, organ accumulation.
Targeting: Phase I imaging with ¹¹¹In-J591 antibody; RGD-targeted liposome efficacy in animal models.
Release: Reductive cleavage of disulphide bonds, acid-labile hydrazone linkers.
Organelle targeting: Nuclear localisation signal peptides, mitochondrial membrane potential exploitation.

Key results: Size effects: Particles <5 nm are rapidly cleared by renal filtration or extravasation. Rigid spherical particles of 100–200 nm have the highest potential for prolonged circulation. Particles >200 nm are filtered by the spleen; >15 μm are mechanically trapped in capillaries. - Shape effects: Filamentous micelles up to 18 μm in length exhibit circulation half-lives of ~5 days, longer than stealth liposomes. In HeLa cells, cylindrical particles with aspect ratio 3 were internalised 4× faster than aspect ratio 1 (150 × 450 nm vs. 200 × 200 nm). Positively charged cubic particles up to 3 μm were internalised by non-phagocytic HeLa cells. - Albumin-coated liposomes: Doxorubicin-loaded albumin-coated liposomes showed >2-fold increase in therapeutic index compared with PEGylated liposomes, with decreased liver, spleen, and heart accumulation and increased tumour accumulation. - RGD-targeted liposomes: Doxorubicin-containing RGD-targeted liposomes exhibited a 15-fold improvement in drug efficacy compared with free drug in a metastasis model. - PSMA targeting: In a Phase I trial of ¹¹¹In-J591 antibody in 27 patients, 20/27 (74%) had at least one known metastatic site successfully imaged; one undiagnosed brain metastasis was identified. - Nuclear targeting: Nuclear pores are ~10 nm, allowing free diffusion of macromolecules <30–40 kDa; they can dilate to ~39 nm. DNA–polylysine complexes up to ~60 nm were delivered to the nucleus when coupled to a nuclear localisation signal. - Mitochondrial targeting: Mitochondrial membrane potential of 130–150 mV can be exploited by cationic species such as triphenylphosphonium. - Stimuli-responsive release: Disulphide-based linkers release cargo in the reducing cytosol; hydrazone linkers release doxorubicin at acidic pH.

Interpretation: The authors conclude that particle size, shape, surface characteristics, and matrix chemistry are central to nanoparticle function and should guide future design. Rigid spherical particles of 100–200 nm are optimal for prolonged circulation, but non-spherical or flexible particles can dramatically extend circulation time. Targeting ligands and stimuli-responsive release mechanisms are essential for selective delivery and activated cargo release. The authors emphasise that overcoming biological barriers requires a highly interdisciplinary approach, and that continued advances in nanoparticle engineering will enable increasingly complex and efficacious therapeutic systems.

Limitations: Limitations inherent to the review:

No primary experimental data; conclusions are synthesised from existing literature.
No systematic search strategy or meta-analysis.
Focus is primarily on polymer-based nanoparticles and oncology; other disease areas and nanocarrier types are less covered.
Clinical translation data are limited; most examples are preclinical or early-phase.

Limitations of the field highlighted by the authors:

PEGylation provides only transient stealth; eventual opsonisation and macrophage clearance occur.
Optimum particle shape parameters have not been fully determined.
Active non-selective targeting (transferrin/folate) suffers from off-target effects because receptors are expressed on some normal cells.
Endosomal escape, tumour heterogeneity, scalability of manufacturing, and control of polydispersity remain significant challenges.
The biotic/abiotic interface is poorly understood; predicting biological responses to nanoparticles remains difficult.
No nanoparticle-based polymeric system had received FDA approval at the time of writing, despite decades of research.

RSC pharmaceutics