Biomaterials Science2019ReviewNon-viral Gene Delivery

Transforming stealthy to sticky nanocarriers: a potential application for tumor therapy

Alidha Gafur, Natalia Kristi, Ali Maruf, Guixue Wang, And Zhiyi Ye29 September 2026DOI 10.1039/c9bm00724e

Summary

Despite decades of nanomedicine development for tumour therapy, less than 1% of systemically administered nanocarriers (NCs) accumulate in solid tumours. This is largely due to protein corona formation during blood circulation, which accelerates clearance and masks targeting ligands. Stealthy (neutral/negatively charged) NCs prolong circulation but hinder cellular uptake, while sticky (positively charged) NCs enhance uptake but are rapidly. Low tumour accumulation baseline: Less than 1% of systemically administered NCs accumulate in solid tumours; nanoparticles of 40–10,000 nm are more prone to liver entrapment (~18–25% ID) than <10 nm particles (~5% ID). -.

Keywords

Nanocarriers Cellular uptake Polymeric Peptides Drug delivery Biodistribution Nanoparticles

Purpose: Despite decades of nanomedicine development for tumour therapy, less than 1% of systemically administered nanocarriers (NCs) accumulate in solid tumours. This is largely due to protein corona formation during blood circulation, which accelerates clearance and masks targeting ligands. Stealthy (neutral/negatively charged) NCs prolong circulation but hinder cellular uptake, while sticky (positively charged) NCs enhance uptake but are rapidly cleared. There is a need for NCs with switchable surface properties—stealthy in circulation and sticky at tumour sites—to overcome this "PEG dilemma" and improve tumour accumulation.

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

If nanocarriers are engineered with charge-switchable surfaces that are stealthy (neutral/negative) during blood circulation and transform to sticky (positive) upon exposure to the acidic tumour microenvironment (pH ~6.5–6.8), then they can simultaneously evade immune clearance, prolong circulation time, enhance tumour accumulation, improve cellular uptake, and enable deeper tumour penetration—ultimately improving therapeutic efficacy.

Aims: Primary Aim: To review recent strategies for developing passive and active charge-switchable nanocarriers—"chameleon-like" drug delivery systems—that reversibly transform their surface from stealthy to sticky for tumour therapy.

Secondary Aims:
To discuss the design principles of smart NCs, including stimuli-responsive (pH, enzyme, ROS, light, magnetic, heat, ultrasound) and charge-switching mechanisms.
To summarise passive charge-switchable NC designs: cleavable bond structures, degradable shells, protonation/deprotonation, and shrinkable/stretchable polymers.
To summarise active charge-switchable NC designs: detachable shells, hybrid active-targeting/charge-switchable shells, shrinkable/stretchable polymers, and charge-switchable ligands.
To identify five key factors for designing optimal charge-switchable NCs and discuss future clinical translation.

Delivery system:

Component: Nanocarrier Types; Examples Discussed: Polymeric nanoparticles, micelles, dendrimers (PAMAM), liposomes, gold nanocages (AuNCs), mixed-shell micelles (MSMs), polyionic complexes

Component: Charge-Switchable Chemistry; Examples Discussed: Citraconic amide, 2,3-dimethylmaleic anhydride (DMMA), hydrazone bonds, cis-aconitic amide, benzoic imine, disulfide bonds, ester bonds, amide bonds, poly(β-amino ester) (PAE), poly(2-(diisopropylamino)ethyl methacrylate) (PDPA), poly(2-(hexamethyleneimino)ethyl methacrylate) (PC7A), zwitterionic carboxy-betaine polymers, polycarboxybetaine methacrylate (PCB)

Component: Payloads; Examples Discussed: Doxorubicin (DOX), indocyanine green (ICG), camptothecin (CPT), therapeutic genes (DNA), photothermal agents

Component: Targeting Ligands; Examples Discussed: RGD peptides, folate (FA), biotin, cell-penetrating peptides (CPPs), VEGFR2-targeting peptides (STP), FK peptides

Component: Key Mechanisms; Examples Discussed: pH-triggered cleavage (tumour extracellular pH ~6.5–6.8; endosomal pH ~5.0), protonation/deprotonation, shrinkable/stretchable polymers, detachable PEG shells, charge-switchable ligands

Component: Routes of Administration; Examples Discussed: Intravenous (i.v.)

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

In vitro studies: Zeta potential changes, cumulative drug release at different pH values (7.4, 6.8, 5.0), cellular uptake.
In vivo models: Tumour-bearing mice (HepG2, etc.), biodistribution, tumour accumulation, survival rate.
Disease context: Solid tumours (liver cancer, breast cancer, etc.).
Group structure: Not applicable; review format.

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

Zeta potential measurements: To confirm charge switching at different pH values.
Drug release assays: Cumulative release profiles at pH 7.4, 6.8, and 5.0.
In vivo fluorescence imaging: To track biodistribution and tumour accumulation of fluorescently labelled NCs.
Quantitative analysis of DOX concentration: In tumour tissues and major organs.
Survival rate analysis: In tumour-bearing mice after photothermal therapy.
Cellular uptake assays: In vitro comparison of NCs with and without charge-switchable properties.

Key results: Low tumour accumulation baseline: Less than 1% of systemically administered NCs accumulate in solid tumours; nanoparticles of 40–10,000 nm are more prone to liver entrapment (~18–25% ID) than <10 nm particles (~5% ID). - DMMA-coated NCs (Du et al.): Zeta potential remained negative at pH 7.4 but became highly positive (nearly +10 mV in 60 min) at pH 6.8. Drug release was much faster at pH 5 than at pH 6.8 or 7.4. - PAMAM-DMMA NCs (Sun et al.): 3-fold enhancement of tumour accumulation compared with non-decorated NCs within 24 h in vivo. - Citraconic amide NCs (Huang et al.): ~70% cleavage of citraconic amide bonds after 5 h at pH 6.6, leading to highly positive surface charge and high tumour accumulation. - PSD-degradable shell NCs: Surface charge changed from −13.8 to +32.2 mV in 10 minutes at pH 6.5; NCs remained in tumour region even after 4 days. - PEG-detachable gene delivery NCs (Guan et al.): Zeta potential increased from +15 mV to +25 mV and size increased from ~150 nm to ~250 nm in <5 minutes at acidic pH; excellent therapeutic efficacy with no mice deaths and stable body weight. - Polyionic complex DOX-NPs (Lv et al.): >5-fold cellular uptake compared to free DOX in vivo; negative charge at pH 7.4 and highly positive at pH <6.8. - Zwitterionic AuNCs (Piao et al.): 80% survival rate after 35 days of photothermal therapy, with longer blood circulation and enhanced tumour accumulation compared to PVP-AuNCs. - RGD-PCB-PDPA/DOX NPs (Huang et al.): 2.25-fold higher tumour accumulation with RGD ligands and 1.52-fold higher without RGD, compared to free DOX after 24 h. - PC7A-based NCs (Chen et al.): 66% longer blood circulation and 23% higher tumour accumulation than non-switchable NCs. - Charge-switchable peptide STP-LS-DOX (Hu et al.): Surface charge shifted from negative to positive at tumour acidic pH, instantly activating VEGFR2 targeting; cellular uptake much higher than naked NCs. - Switching time: Several designs switch in 2–10 minutes; others need 1–2 hours or more. - Tumour vs. organ accumulation: Cleavable-bond passive NCs showed 3.4–4.4-fold higher accumulation in tumour than liver and 1.89–4.12-fold higher than other major organs. Hybrid active targeting/charge-switchable design showed 4-fold higher tumour accumulation than liver and 8-fold higher than other organs.

Interpretation: The authors conclude that charge-switchable NCs—"chameleon-like" drug delivery systems—have shown great promise in preclinical studies for overcoming biological barriers, prolonging blood circulation, and enhancing tumour accumulation. They identify five key factors for optimal design:

1. Stealthy in circulation: Neutral or negative charge to avoid protein corona and immune clearance. 2. Sticky at tumour site: Negative charge converts to highly positive in the tumour area to enhance cellular uptake. 3. Fast charge conversion: Rapid switching (within minutes) is needed to prevent NCs from flowing back into the bloodstream due to high interstitial fluid pressure. 4. Reversible effect: NCs should be able to regain stealthy properties and retarget tumour tissues if they fail to penetrate. 5. Passive vs. active design: Active NCs may offer better tumour accumulation due to specific ligand-receptor interactions.

The next step for these chameleon-like drug delivery systems is to enter clinical trials.

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 preclinical studies; clinical translation data are limited.
Heterogeneity of NC designs, tumour models, and payloads makes direct comparisons difficult.

Limitations of the field highlighted by the authors:

Low tumour accumulation: Less than 1% of administered NCs reach solid tumours; most are trapped in liver, spleen, and other organs.
Protein corona formation: Blocks targeting ligands and accelerates RES clearance, reducing the benefit of active targeting.
PEG dilemma: PEGylation prolongs circulation but hinders cellular uptake; charge-switchable designs aim to overcome this but add complexity.
Interstitial fluid pressure: High pressure inside solid tumours pushes NCs back into the bloodstream; fast charge conversion is needed to anchor NCs.
Switching time variability: Some designs switch in 2–10 minutes, but others need 1–2 hours or more; slow switching may limit tumour penetration.
Reversibility requirements: NCs need reversible charge switching to retarget tumour tissues if they fail to penetrate, which is technically challenging.
Clinical translation: Most studies are preclinical; no charge-switchable NC has yet entered clinical trials. Long-term safety, scalability, and regulatory pathways remain unproven.
Size and shape effects: Nanoparticle size and shape also influence biodistribution (e.g., cage- and disk-like particles accumulate ~90–100% ID in spleen), but the review focuses primarily on surface charge.

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