Bioorthogonal Targeting Strategies in Cancer Nanomedicine

Bioorthogonal targeting strategies harness chemical reactions that proceed in living systems without perturbing native biochemical processes, enabling precise localisation of therapeutic payloads to tumour sites. Central to these approaches is the metabolic installation of non-natural functional groups—commonly azides or alkynes—onto cellular glycans or proteins, which then serve as handles for the selective conjugation of drug-loaded nanocarriers via strain-promoted azide–alkyne cycloaddition or other catalyst-free “click” reactions. Beyond click chemistry, supramolecular host–guest recognition modules, such as cucurbit[7]uril assemblies, exploit the elevated concentrations of tumour-associated metabolites (for example, polyamines) to guide liposomal or polymeric nanoformulations into malignant tissue. Two-step targeting paradigms have emerged, in which an initial administration of a metabolic labelling agent or cell-based vehicle accumulates a synthetic receptor at the tumour, followed by delivery of a complementary nanoparticle bearing the reactive partner. These innovations afford high specificity, improved tissue penetration and modular adaptability, opening new avenues for combination regimens that integrate chemotherapy, immunotherapy or imaging. Despite challenges in scale-up, biodistribution control and immunogenicity, bioorthogonal targeting continues to redefine the precision and efficacy of cancer nanomedicine on a global scale.

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Bioorthogonal Targeting Strategies in Cancer Nanomedicine publication trend

The graph below shows the total number of articles in bioorthogonal targeting strategies in cancer nanomedicine across all publications each year (not limited to Nature Index journals).

Technical terms

Bioorthogonal chemistry: Chemical reactions that occur inside living organisms without interfering with native biological functions.

Metabolic labelling: Incorporation of non-natural chemical groups into biomolecules via cellular metabolic pathways to introduce reactive handles.

Strain-promoted azide–alkyne cycloaddition (SPAAC): A copper-free click reaction between strained alkynes and azides, used for bioconjugation in vivo.

Host–guest interaction: Non-covalent binding between a molecular “host” (for example, cucurbit[7]uril) and a complementary “guest” (such as tumour-associated polyamines).

Two-step targeting: A strategy in which a synthetic receptor is first localised at the tumour, followed by administration of a complementary reactive nanoparticle.

Dibenzocyclooctyne (DBCO): A strained alkyne employed in catalyst-free click chemistry for conjugation to azide-modified targets.

References

1. Tumor polyamines as guest cues attract host-functionalized liposomes for targeting and hunting via a bio-orthogonal supramolecular strategy. Theranostics (2023).
2. Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry. Signal Transduction and Targeted Therapy (2022).