A Recent Review on Cancer Nanomedicine

Cancer accounts for roughly one in six deaths worldwide, with 19.3 million new cases and over 10 million deaths in 2020. Standard diagnostic and therapeutic paradigms include screening, surgery, radiation, and chemotherapy, supplemented by immunotherapy, hormone therapy, gene therapy, and stem cell therapy. Chemotherapy remains a mainstay, especially in advanced disease, but is hampered by poor tumor specificity, severe dose-dependent toxicities, poor solubility and bioavailability, stability issues, and the development of resistance. Nanotechnology offers a means to circumvent many of these limitations by encapsulating, adsorbing, or conjugating drugs within nanocarriers (typically <500 nm), enhancing bioavailability of poorly soluble drugs, modulating pharmacokinetics, and promoting tumor-selective accumulation. The enhanced permeability and retention (EPR) effect underpins many nanomedicines by exploiting leaky tumor vasculature and poor lymphatic drainage for passive targeting, leading to improved therapeutic indices. However, EPR heterogeneity, variable tumor perfusion, and stromal barriers limit universal applicability. Consequently, next-generation platforms leverage ligand-mediated active targeting and tumor microenvironment (TME)-responsive release, while tuning nanocarrier size, shape, and surface chemistry (e.g., PEGylation) to optimize circulation and biodistribution.

The review surveys major nanocarrier classes and their oncologic applications:

• Lipid-based nanocarriers: Liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) are highlighted for biocompatibility, high payload capacity for hydrophilic/hydrophobic agents, controlled release, and ease of surface functionalization. PEGylated “stealth” liposomes reduce opsonization and RES clearance, prolonging circulation (e.g., Doxil). Active targeting using folate, hyaluronic acid, antibodies, and aptamers improves tumor uptake. Stimuli-responsive and theranostic liposomes enable image-guided chemo/phototherapy. SLNs and NLCs address stability and loading constraints; ligand-modified and pH-responsive SLNs/NLCs show enhanced pharmacokinetics and efficacy. Comparative studies indicate NLCs can outperform liposomes in some tumor models and delay metastasis.
• Inorganic nanocarriers: Iron oxide, gold, mesoporous silica, graphene oxide, carbon nanotubes, and related materials offer structural control, high stability, diverse surface chemistry, and unique magnetic/optical properties for drug delivery and adjunct modalities (MRI, MPI, PTT, PDT, hyperthermia). Iron oxide nanoparticles (FeNPs/SPIONs) serve as imaging agents and drug/gene carriers; coatings (PEG, PLA, PLGA, chitosan, casein, PCL) improve colloidal stability and immune evasion. Magnetic targeting, ferroptosis induction, and theranostic hybrids (e.g., mesoporous silica–coated FeNPs with pH/redox responsiveness) are discussed. Gold nanoparticles (AuNPs) enable tunable surface plasmon resonance for NIR photothermal ablation, including pH-triggered aggregation for enhanced deep-tissue PTT, and co-delivery of chemotherapeutics and siRNA. Mesoporous silica nanoparticles (MSNs) offer high surface area, tunable pores, amorphization of hydrophobic drugs, and ligand-mediated, pH/redox-responsive release. Carbon nanotubes (SWCNTs/MWCNTs), after surface functionalization (e.g., PEGylation, antibodies), support drug loading, imaging, and PTT, including targeting of resistant phenotypes. Graphene oxide nanoparticles provide large surface area, improved aqueous stability, and biodegradability; conjugates with Fe3O4 or peptide ligands enable imaging, magnetic targeting, and organelle-specific delivery (e.g., mitochondrial targeting) with enhanced apoptosis.
• Polymeric nanoparticles: FDA-approved and investigational polymers (PLGA, PLA, PGA, PCL, PLGA-PEG; natural polymers like chitosan, alginate, gelatin, albumin) enable high encapsulation, tunable degradation and release, scalable manufacture, and facile ligand decoration. Examples include co-loaded PLGA systems (docetaxel + LY294002), RGD-targeted PLGA nanoparticles for cisplatin, and coated systems (e.g., chitosan/folate) to mitigate burst release and enhance uptake. Chitosan-based platforms (PEGylated, antibody- or folate/DPA-modified) support targeted chemo–gene co-delivery (CRISPR/Cas9 or RNAi). Polymeric micelles (PLGA-PEG-RA; PEG–PBAE–PEG; PEG-PLL) solubilize hydrophobes, support pH-responsive release, and mediate gene delivery. Dendrimers (e.g., PAMAM, PLL, PPI) allow controlled architectures, multivalent conjugation/encapsulation, and surface tuning (PEGylation, glycotargeting) for improved biocompatibility and targeting.
• Biological nanocarriers: Exosomes (40–150 nm) derived from various cells act as natural carriers conveying parental cell signals and can be engineered for drug/gene loading via electroporation, sonication, extrusion, etc. They demonstrate improved targeting (e.g., BM-MSC homing), capacity to modulate TME and immunity, enable theranostics (e.g., MPI tracking), and overcome MDR (e.g., exosome-loaded paclitaxel). Surface functionalization (e.g., hyaluronan) augments receptor-mediated uptake (CD44). The review also catalogs approved nanomedicines (e.g., Doxil/Caelyx, Abraxane, Onivyde, Vyxeos, Genexol-PM, NanoTherm, Hensify) and ongoing clinical trials across platforms (liposomal, polymeric micelles, gold nanoparticles, exosomes, lipid nanoparticles), noting most clinical candidates still rely on EPR-mediated accumulation, with growing exploration of active targeting and stimuli-responsiveness.

• Nanocarriers mitigate key limitations of chemotherapy by improving solubility, stability, pharmacokinetics, tumor accumulation, and reducing systemic toxicity through passive (EPR) and active/TME-responsive targeting.
• PEGylated liposomes prolong circulation and enhance exposure: Doxil showed biphasic clearance (initial t1/2 1–3 h), terminal t1/2 42–46 h; free doxorubicin initial t1/2 ~5 min, terminal t1/2 25–30 h; ~300-fold higher AUC vs free drug.
• Active targeting and stimuli-responsiveness improve efficacy: folate-conjugated pH-responsive irinotecan liposomes increased tumor uptake and anticancer activity vs free drug; theranostic thermosensitive liposomes enabled NIR-triggered release and multimodal imaging with effective tumor inhibition.
• SLNs/NLCs: RGD-modified pH-sensitive doxorubicin SLNs achieved drug loading 9.8% and encapsulation efficiency 98.5%; at pH 5 showed biphasic release and 5.58-fold higher AUC vs doxorubicin solution with superior tumor inhibition. NLCs outperformed liposomal and free doxorubicin in reducing 4T1 breast tumor growth and delayed lung metastases. Folate-modified resveratrol NLCs (size 88.3 ± 3.1 nm; EE 88.0 ± 2.6%) improved PK (t1/2 12.04 h; AUC 57.92 µg·mL−1·h) vs unmodified NLCs (t1/2 10.38 h; AUC 27.11) and free drug (t1/2 0.98 h; AUC 6.37), with receptor-specific cytotoxicity.
• Inorganic platforms: DOX@MMSN-SS-PEI-cit (pH/redox-responsive FeNP–MSN hybrid) exhibited charge reversal in acidic TME and GSH-dependent release (98.1% at 10 mM GSH vs 42.4% at 1 mM and 15.3% at 0 mM in 72 h), enhanced 4T1 uptake at pH 6.5, MRI visibility, and superior tumor inhibition vs free DOX. pH-responsive AuNPs aggregated at acidic pH, shifting SPR and boosting PTT (temperature increase ≥30°C at pH 5.5 vs 9–12°C at pH 7.4 upon NIR), selectively killing cancer cells while sparing healthy cells. AuNP co-delivery (Dox + Bcl-2 siRNA) reduced Bcl-2 expression by ~40% at 50 nM siRNA and inhibited proliferation/migration in TNBC cells. Targeted SWCNTs (IGF-1R) showed peak tumor-to-background ratio at 18 h post-injection with retention up to 48 h and effective PTT.
• Exosomes: Exosome-loaded paclitaxel (exoPTX) increased cytotoxicity in MDR cells vs Taxol/free drug and significantly inhibited pulmonary metastases in vivo (p < 0.05). BM-MSC exosomes co-delivering galectin-9 siRNA and oxaliplatin reprogrammed TME (Mφ polarization, CTL recruitment, Treg downregulation) and achieved efficient PDAC tumor inhibition; iron oxide–loaded exosomes enabled magnetic hyperthermia-induced apoptosis.
• Clinical translation: Multiple nanomedicines have regulatory approval across indications (e.g., Doxil/Caelyx 1995, Abraxane 2005, Onivyde 2015, Vyxeos 2017, NanoTherm 2010/2018, Hensify 2019), with numerous ongoing trials for liposomal, polymeric, gold, exosome, and LNP platforms. Despite progress, most clinical candidates still depend on EPR, with active/stimuli-responsive systems emerging.
• Mechanistic insight: While EPR underpins many designs, heterogeneity limits applicability; active trans-endothelial transport may dominate nanoparticle tumor entry (~97% reported in one study), motivating designs that exploit biological transport pathways.

The review synthesizes evidence that nanomedicine can address central failings of conventional chemotherapy—poor tumor specificity, suboptimal pharmacokinetics, and systemic toxicity—by leveraging passive EPR-based accumulation and advancing toward active receptor targeting and TME-responsive delivery. Across lipid, polymeric, inorganic, and biological platforms, preclinical and clinical data demonstrate improved exposure (e.g., Doxil’s markedly increased AUC), controlled and triggered release, enhanced intratumoral uptake, and integration with imaging and adjunct modalities (PTT, PDT, hyperthermia) for theranostics. Case studies (e.g., targeted SLNs/NLCs, pH/redox-responsive hybrids, exosome-mediated delivery overcoming MDR and reprogramming TME) show that rational design tailored to tumor biology can enhance efficacy and safety. However, variability in EPR, stromal barriers, and interpatient heterogeneity limit universal performance, underscoring the need for active transport exploitation, personalized targeting ligands, and stimuli-responsive systems. The clinical pipeline indicates steady translation for established platforms (liposomes, albumin NPs, polymeric micelles), with newer modalities (gold, exosomes, LNPs) entering early trials. Overall, nanocarriers offer a route to higher therapeutic indices and multimodal treatment paradigms, but translation demands addressing biocompatibility, manufacturability, and model relevance.

Nanomedicine offers solutions to key limitations of traditional cancer chemotherapy by enhancing targeting, local efficacy, and safety; enabling controlled and stimuli-responsive release; improving diagnostic sensitivity and image guidance; and facilitating combination and theranostic strategies. Co-delivery approaches can overcome resistance, and nanotechnology increasingly supports cancer immunotherapy. The outlook is promising, with advances in materials engineering and data-driven design accelerating progress. Realizing clinical potential will require comprehensive evaluation of efficacy and toxicity in appropriate models, robust biocompatibility assessment, and scalable, reproducible manufacturing to increase the rate of successful translation.

Key limitations and challenges include: (1) Reliance on heterogeneous and often patient-specific EPR effects, with diminished translatability from small animal models to humans; (2) Uncertain long-term biocompatibility/toxicity for diverse nanomaterials and propensity for RES accumulation (liver, spleen, lungs), necessitating extensive chronic safety studies; (3) Early-stage neglect of sterility and endotoxin control, critical for IV products; (4) Manufacturing complexity and scale-up challenges for multifunctional/surface-modified nanocarriers, with variability in formulation processes and constraints on drug loading/reproducibility; (5) Limited predictive value of conventional animal tumor models for human pharmacokinetics and efficacy; (6) High production costs and environmental impacts that may impede clinical adoption despite therapeutic advantages.