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Advancing engineering design strategies for targeted cancer nanomedicine

Nature Reviews Cancer volume 25, pages 657–683 (2025)Cite this article

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Abstract

Engineered nanoparticles have greatly expanded cancer treatment by encapsulating and delivering therapeutic and diagnostic agents, otherwise limited by poor pharmacokinetics and toxicity, to target tumour cells. Leveraging our increased understanding of the tumour microenvironment, nanomedicine has expanded to additionally target key tissues and cells implicated in tumorigenesis, such as immune and stromal cells, to improve potency and further mitigate off-target toxicities. To design nanocarriers that overcome the body’s physiological barriers to access tumours, the field has explored broader routes of administration and nanoparticle design principles, beyond the enhanced permeation and retention effect. This Review explores the advantages of non-covalent surface modifications of nanoparticles, along with other surface modifications, to modulate nanoparticle trafficking from the injection site, into tumour and lymphoid tissues, to the target cell, and ultimately its subcellular fate. Using electrostatic or other non-covalent techniques, nanoparticle surfaces can be decorated with native and synthetic macromolecules that confer highly precise cell and tissue trafficking. Rational design can additionally minimize detection and clearance by the immune system and prolong half-life — key to maximizing efficacy of therapeutic cargos. Finally, we outline how cancer nanomedicine continues to evolve by incorporating learnings from novel screening technologies, computational approaches and patient-level data to design efficacious targeted therapies.

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Fig. 1: Targeted cancer nanomedicine aims to develop nano-systems that address and surpass the multiple levels of biological barriers.
Fig. 2: Nanoparticles must navigate different biological barriers to reach tumour tissue, depending on the route of administration.
Fig. 3: Targeting the cells and matrix within the tumour microenvironment using nanoparticles.
Fig. 4: Non-covalent surface modifications enable the adsorption of various surface chemistries onto nanoparticle substrates, to confer various trafficking advantages.
Fig. 5: Nanoparticle surface chemistry dictates mechanisms of endocytosis and intracellular trafficking.

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Acknowledgements

N.N. and V.F.G. acknowledge funding from the NSF Graduate Research Fellowship Program under grant no. 2141064. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the NSF. V.F.G. acknowledges additional support from the MIT UCEM–Alfred P. Sloan Foundation Scholarship Program. We would additionally like to thank T. Dacoba, J. Kaskow, A. Stoneman and A. Pickering for their review of this manuscript.

Author information

Author notes

  1. These authors contributed equally: Victoria F. Gomerdinger, Namita Nabar.

Authors and Affiliations

  1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Victoria F. Gomerdinger, Namita Nabar & Paula T. Hammond

  2. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Victoria F. Gomerdinger, Namita Nabar & Paula T. Hammond

  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Victoria F. Gomerdinger, Namita Nabar & Paula T. Hammond

  4. Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA, USA

    Paula T. Hammond

Authors
  1. Victoria F. Gomerdinger
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  2. Namita Nabar
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  3. Paula T. Hammond
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Paula T. Hammond.

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Competing interests

P.T.H. is the co-founder and a former member of the Board of LayerBio, Inc., a member of the Board of Alector Therapeutics, the Board of Sail Biomedicine, a Flagship company, and a former member of the Scientific Advisory Board of Moderna Therapeutics.

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Nature Reviews Cancer thanks Debra Auguste and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Aggregation

The formation of heterogeneous clusters of nanoparticles, often due to instability, which impedes uptake, tolerability and targeting efficiency.

Bottlebrush

Polymer architecture characterized by densely branched macromonomer chains grafted onto a polymeric backbone.

Endocytosis

Engulfment of foreign material by a cell, generally through membrane invagination.

Endosomal escape

The rate-limiting step for intracellular nanoparticle delivery, whereby the nanoparticle exits from endocytic vesicles into the cytoplasm of the cell.

Host–guest interactions

High-affinity complexes that form between two molecular species and are held together by non-covalent interactions and complementary structural relationships.

Lipid nanoparticle

(LNP). A self-assembled nanoparticle composed of ionizable cationic lipids that electrostatically encapsulate cargos, commonly nucleic acids, within internal micellar structures.

Macropinocytosis

Nonspecific endocytosis in which a cell engulfs a large volume of extracellular fluid.

Micelle

A self-assembled nano-scale particle composed of amphiphilic molecules (with hydrophobic and hydrophilic regions).

Microneedle

A delivery platform comprised of micro-scale needles that can be coated with compounds, typically to facilitate transdermal or intradermal drug delivery.

Nanoparticles

Particles most strictly defined as having size of 1–100 nm, but often including particles with sizes of several hundred nanometres.

Opsonization

The adsorption of proteins recognizable by phagocytic cells onto nanoparticle surfaces.

Organoid

Self-organizing 3D cellular structure composed of multiple cell types, representing a simpler version of an organ while recapitulating many of its functions.

Organ-on-a-chip

A microfluidic platform in which organized, micro-scale cellular structures are grown, to recapitulate characteristics of the corresponding tissue.

Phagocytosis

Cellular engulfment of particles or debris >500 nm in diameter.

Polyethylene glycol

(PEG). A hydrophilic neutral polymer incorporated onto many therapeutics, including nanoparticle surfaces, to decrease protein adsorption and improve circulation time.

Polyplex

A nanoparticle held together through electrostatic interactions between cationic polymers and anionic cargos (nucleic acids).

Quantum dot

A nanoparticle composed of semiconducting materials which have unique optical or electronic properties.

Stealth

The ability of nanoparticles to evade detection and clearance by immune cells and remain in circulation for extended time.

Transcytosis

A cellular transport mechanism whereby material is taken up from one side of a cell, traffics across its cytoplasm, and is then released on the opposite side of the cell.

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Gomerdinger, V.F., Nabar, N. & Hammond, P.T. Advancing engineering design strategies for targeted cancer nanomedicine. Nat Rev Cancer 25, 657–683 (2025). https://doi.org/10.1038/s41568-025-00847-2

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