Nature Reviews Materials2021ReviewDrug Delivery

Targeted drug delivery strategies for precision medicines

Mandana T. Manzari, Yosi Shamay, Hiroto Kiguchi, Neal Rosen, Maurizio Scaltriti, And Daniel A. Heller29 September 2026DOI 10.1038/s41578-020-00269-6

Summary

Precision medicine has transformed cancer therapy by enabling molecular profiling and optimized drug design, but clinical translation of many precision therapeutics is hindered by pharmacological limitations, including toxicities and drug resistance. Drug delivery materials can modulate a drug’s pharmacokinetics, biodistribution, and toxicity without compromising its molecular target engagement, offering a route to improve the therapeutic index. Kinase inhibitor landscape: More than 50 small-molecule protein kinase inhibitors have been FDA-approved, with the majority developed as targeted cancer therapeutics. - Dose-limiting toxicity example: In a phase I trial.

Keywords

Drug delivery Polymeric Nanoparticles siRNA Biodistribution Nanocarriers Targeted delivery

Purpose: Precision medicine has transformed cancer therapy by enabling molecular profiling and optimized drug design, but clinical translation of many precision therapeutics is hindered by pharmacological limitations, including toxicities and drug resistance. Drug delivery materials can modulate a drug’s pharmacokinetics, biodistribution, and toxicity without compromising its molecular target engagement, offering a route to improve the therapeutic index of cancer drugs and clinical outcomes.

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

If drug delivery strategies are integrated into precision medicine—modulating pharmacokinetics, biodistribution, toxicity, and combination delivery—then the therapeutic index of cancer drugs can be improved, extending precision to the location and timing of therapy and ultimately improving patient outcomes.

Aims: Primary Aim: To highlight recent progress in precision therapeutics and drug delivery, and identify opportunities for delivery strategies to improve the therapeutic index of cancer drugs and clinical outcomes.

Secondary Aims:
To focus on kinase inhibitors as a model class for integrating targeted drugs with targeted delivery systems.
To elucidate the major limitations of precision medicines (dose-limiting toxicities, on-target/off-target toxicity, pharmacokinetic variability, resistance) and match each to potential delivery solutions.
To briefly introduce other precision medicine classes, including monoclonal antibodies, nucleic acid therapies, and immunotherapies.
To review clinical trials involving delivery systems and discuss regulatory and translational challenges.

Delivery system:

Component: Nanocarriers; Examples Discussed: Liposomes, polymeric nanoparticles, polymer–drug conjugates, dendrimers, silica nanoparticles, gold nanoparticles/nanoshells, carbon nanostructures, nanocrystals, polymeric micelles, protein nanoparticles, stimuli-responsive hydrogels, microneedle patches, slow-release matrices/wafers

Component: Payloads; Examples Discussed: Kinase inhibitors (e.g., AZD2811, MEK163, alpelisib, PD0325901), chemotherapeutics (doxorubicin, paclitaxel, cisplatin), nucleic acids (siRNA, miRNA, mRNA, pDNA), gene-editing tools (CRISPR-Cas9, ZFNs, TALENs), immunotherapeutics

Component: Targeting Strategies; Examples Discussed: Passive targeting via enhanced permeability and retention (EPR); active targeting to transferrin receptor, folate receptor, PSMA, P-selectin, E-selectin, integrins (RGD), EGFR, CD38, etc.; organ-specific targeting (liver, lungs, kidneys, bone, brain)

Component: Drug Loading; Examples Discussed: Nanocrystals: 75–90%; liposomal NPs: 0.5–20%; polymeric NPs: 0.5–20%; polymer–drug conjugates: 1–10%; dendrimers: 1–5%; protein NPs: 5–10%; inorganic NPs: 1–25%

Approach: This is a narrative review synthesizing preclinical and clinical literature. No primary experimental data are presented. The review covers:

Model systems: Mouse tumor models, patient-derived xenografts (PDX), immortalized cell lines, and human clinical trials (phase I–III).
Disease contexts: Multiple cancers, including breast, lung, colorectal, melanoma, chronic myeloid leukemia, head and neck squamous cell carcinoma, ovarian cancer, and others.
Group structure: Not applicable; review format.
Clinical trials: Includes NCT01455389 (TUSC2-DOTAP:cholesterol nanoparticles), NCT01262235 (TKM-080301), NCT01591356 (EphA2 siRNA), NCT02716012 (MTL-CEBPA), NCT01960348 (patisiran), NCT02975882 (nab-rapamycin), NCT02646319 (nab-rapamycin), NCT03168061 (epirubicin micelles), NCT03742713 (CPC634 docetaxel), NCT03382340 (IMX-110).

Key methods: As a review, the “methods” are literature synthesis and comparative analysis. Headline data cited from primary studies were generated using:

Pharmacokinetic profiling: Absorption, half-life, plasma protein binding, recommended dose.
Biodistribution and tumor accumulation: Radiolabeled nanoparticles, imaging.
Drug loading quantification: Mass of drug per mass of total nanoparticle.
Efficacy assessments: Tumor growth inhibition, signaling pathway inhibition (MAPK, PI3K), apoptosis, disease stabilization.
Toxicity assessments: Dose-limiting toxicities, myelosuppression, hyperglycemia, skin toxicity, hepatotoxicity, cardiotoxicity.
Clinical trial endpoints: Safety, tolerability, maximum tolerated dose, recommended phase II dose, antitumor activity.

Key results: Kinase inhibitor landscape: More than 50 small-molecule protein kinase inhibitors have been FDA-approved, with the majority developed as targeted cancer therapeutics. - Dose-limiting toxicity example: In a phase I trial of LY2606368 (CHK1 inhibitor), 7 of 45 patients experienced dose-limiting toxicity at doses ≥120 mg/m²; the recommended phase II dose was lowered to 105 mg/m². - Accurins (AZD2811 nanoparticles): Controlled release of Aurora B kinase inhibitor over >1 week, prolonged target inhibition in tumors, improved preclinical efficacy, and a favorable safety profile in a phase I trial. - P-selectin-targeted nanoparticles: Delivered MEK163 to colorectal tumors, facilitated target inhibition in tumors, prevented drug accumulation in skin, and improved therapeutic index. P-selectin-targeted alpelisib plus radiotherapy abrogated hyperglycemia and achieved durable responses in HNSCC PDX models. - Dual-pathway nanoparticle delivery: Layer-by-layer nanoparticles co-delivering MEK and PI3K inhibitors produced 3.9-fold and 9.4-fold reductions in tumor-specific MAPK and PI3K pathway signaling, respectively, with reduced dose-limiting hepatotoxicity compared with free drug combination. - Pharmacokinetic variability: Recommended daily doses range from 2 mg/day (trametinib) to ~1,920 mg/day (vemurafenib), with a median of 250 mg/day. About 25% of 41 listed kinase inhibitors have half-lives ≤10 h; about 50% have half-lives ≥24 h. Vismodegib, vandetanib, and sonidegib have half-lives of 12, 19, and 28 days, respectively. - Drug loading limitations: Most nanoparticles exhibit relatively low drug-loading efficiencies (e.g., polymeric and liposomal NPs: 0.5–20%; polymer–drug conjugates: 1–10%), whereas nanocrystals achieve 75–90%. - Clinical milestone: Patisiran, an siRNA formulated in lipid nanoparticles, was the first siRNA therapy approved by the FDA in 2018 for hereditary transthyretin-mediated amyloidosis.

Interpretation: The authors conclude that integrating materials science and cancer biology can translate to improved patient outcomes. Drug delivery strategies can extend precision medicine beyond molecular targeting to include the location (tissue/organ) and timing (controlled release) of therapy. While nanomedicine has advanced for chemotherapeutics and RNA delivery, the targeted delivery of small-molecule precision drugs—especially kinase inhibitors—remains underexplored. The authors urge pharmacologists and cancer biologists to leverage drug delivery to overcome barriers to clinical success.

Limitations: Limitations inherent to the review:

No primary experimental data; conclusions are synthesized from existing literature.
Not intended as a comprehensive review of kinase inhibitor therapies or drug delivery systems.
Focus is primarily on kinase inhibitors; other precision medicine classes are discussed briefly.
No systematic search strategy or meta-analysis.

Limitations of the field highlighted by the authors:

Low drug-loading efficiency of many nanocarriers complicates integration with diverse drug chemistries.
Few clinical trials have tested nanomedicine delivery of small-molecule precision drugs (e.g., kinase inhibitors, anti-androgen therapies).
Resistance mechanisms and compensatory pathway activation limit durable responses.
Additive or synergistic toxicities of combination therapies can require dose de-escalation and discontinuation.
EPR effect heterogeneity across tumor types and patients; not fully characterized in humans.
Regulatory confusion: Nanoparticle versions of existing drugs are usually regarded as new drugs requiring an Investigational New Drug application; vehicle components may be considered separately.
Patient selection and correlates are needed to identify responders to nanomedicines; imaging methods and biomarkers are still in development.