# Smart Nanoformulations for Oncology: A Review on Overcoming Biological Barriers with Active Targeting, Stimuli-Responsive, and Controlled Release for Effective Drug Delivery

**Authors:** Srikanth Basety, Renuka Gudepu, Aditya Velidandi

PMC · DOI: 10.3390/pharmaceutics18020196 · 2026-02-02

## TL;DR

This review explores smart nanoformulations for cancer drug delivery, focusing on overcoming biological barriers through targeted and responsive design.

## Contribution

The paper introduces a hierarchical design pipeline for nanocarriers that integrates biological barriers and nanoparticle properties for effective drug delivery.

## Key findings

- A multi-tiered tumor microenvironment is identified as a key obstacle for drug delivery.
- Nanoparticle properties influence in vivo identity and targeting through the protein corona.
- Responsive and immuno-nanoformulations are proposed as strategies to enhance therapeutic efficacy.

## Abstract

Effective drug delivery in oncology is challenged by a hierarchy of biological barriers—from abnormal vasculature and dense stroma to cellular immunosuppression and specialized interfaces like the blood–brain barrier. This review provides a contemporary analysis of smart nanoformulations through the lens of a rational, stage-gated design pipeline. We first deconstruct the solid tumor microenvironment as a multi-tiered obstacle (systemic, stromal, cellular), establishing a barrier-specific foundation for nanocarrier design. The core of the review articulates an architectural toolkit, detailing how intrinsic nanoparticle properties precondition in vivo identity via the protein corona, which in turn informs the selection of advanced ligands for cellular targeting and programmed intracellular trafficking. This integrated framework sets the stage for exploring sophisticated applications, including endogenous and externally triggered responsive systems, bio-orthogonal activation, immuno-nanoformulations, and combination strategies aimed at overcoming multidrug resistance. By synthesizing these components into a cohesive design philosophy, this review moves beyond a catalog of advances to offer a blueprint for engineering next-generation nanotherapeutics. We critically assess the translational landscape and contend that this hierarchical design approach is essential for developing more effective, personalized, and clinically viable cancer treatments.

## Linked entities

- **Diseases:** cancer (MONDO:0004992)

## Full-text entities

- **Genes:** FGB (fibrinogen beta chain) [NCBI Gene 2244] {aka HEL-S-78p}, BAX (BCL2 associated X, apoptosis regulator) [NCBI Gene 581] {aka BCL2L4}, Casp3 (caspase 3) [NCBI Gene 12367] {aka A830040C14Rik, AC-3, CASP-3, CC3, CPP-32, CPP32}, Cd44 (CD44 antigen) [NCBI Gene 12505] {aka HERMES, Ly-24, Pgp-1}, CASP7 (caspase 7) [NCBI Gene 840] {aka CASP-7, CMH-1, ICE-LAP3, LICE2, MCH3}, Itgax (integrin alpha X) [NCBI Gene 16411] {aka Cd11c, Cr4, N418}, LEF1 (lymphoid enhancer binding factor 1) [NCBI Gene 51176] {aka ECTD1, ECTD17, LEF-1, TCF10, TCF1ALPHA, TCF7L3}, H2 (histocompatibility-2, MHC) [NCBI Gene 111364] {aka H-2, MHC-II}, ANXA5 (annexin A5) [NCBI Gene 308] {aka ANX5, CPB-I, ENX2, HEL-S-7, PP4, RPRGL3}, ACE (angiotensin I converting enzyme) [NCBI Gene 1636] {aka ACE1, CD143, DCP, DCP1}, NRAS (NRAS proto-oncogene, GTPase) [NCBI Gene 4893] {aka ALPS4, CMNS, N-ras, NCMS, NRAS1, NS6}, Itgam (integrin alpha M) [NCBI Gene 16409] {aka CD11b/CD18, CR3, CR3A, Cd11b, F730045J24Rik, Ly-40}, Cd80 (CD80 antigen) [NCBI Gene 12519] {aka B71, Cd28l, Ly-53, Ly53, MIC17, TSA1}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, CASP9 (caspase 9) [NCBI Gene 842] {aka APAF-3, APAF3, ICE-LAP6, MCH6, PPP1R56}, BMP2 (bone morphogenetic protein 2) [NCBI Gene 650] {aka BDA2, BMP2A, SSFSC, SSFSC1}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, Tfrc (transferrin receptor) [NCBI Gene 22042] {aka 2610028K12Rik, CD71, E430033M20Rik, Mtvr1, TFR, TFR1}, PRMT5 (protein arginine methyltransferase 5) [NCBI Gene 10419] {aka HRMT1L5, HSL7, IBP72, JBP1, SKB1, SKB1Hs}, CXADRP1 (CXADR pseudogene 1) [NCBI Gene 653108] {aka CAR, CXADRP}, NUCLEOLIN (nucleolin multifunctional protein) [NCBI Gene 4691] {aka C23, NCL, Nsr1}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, Pdcd1 (programmed cell death 1) [NCBI Gene 18566] {aka Ly101, PD-1, Pdc1}, Mmp9 (matrix metallopeptidase 9) [NCBI Gene 17395] {aka B/MMP9, Clg4b, Gel B, MMP-9, pro-MMP-9}, CDK6 (cyclin dependent kinase 6) [NCBI Gene 1021] {aka MCPH12, PLSTIRE}, EMP2 (epithelial membrane protein 2) [NCBI Gene 2013] {aka XMP}, ADAM8 (ADAM metallopeptidase domain 8) [NCBI Gene 101] {aka CD156, CD156a, MS2}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, TRBV20OR9-2 (T cell receptor beta variable 20/OR9-2 (non-functional)) [NCBI Gene 6962] {aka CDR3, TCRBV20S2, TCRBV2O, TCRBV2S2O}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, Cd274 (CD274 antigen) [NCBI Gene 60533] {aka A530045L16Rik, B7h1, Pdcd1l1, Pdcd1lg1, Pdl1}, Mki67 (antigen identified by monoclonal antibody Ki 67) [NCBI Gene 17345] {aka D630048A14Rik, Ki-67, Ki67}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Cd3e (CD3 antigen, epsilon polypeptide) [NCBI Gene 12501] {aka CD3, CD3epsilon, T3e}, Cd47 (CD47 antigen (Rh-related antigen, integrin-associated signal transducer)) [NCBI Gene 16423] {aka 9130415E20Rik, B430305P08Rik, IAP, Itgp}, Adgre1 (adhesion G protein-coupled receptor E1) [NCBI Gene 13733] {aka DD7A5-7, EGF-TM7, Emr1, F4/80, Gpf480, Ly71}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, TF (transferrin) [NCBI Gene 7018] {aka HEL-S-71p, PRO1557, PRO2086, TFQTL1}, ALB (albumin) [NCBI Gene 213] {aka FDAHT, HSA, PRO0883, PRO0903, PRO1341}, CXCL11 (C-X-C motif chemokine ligand 11) [NCBI Gene 6373] {aka H174, I-TAC, IP-9, IP9, SCYB11, SCYB9B}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, Kras (Kras proto-oncogene, GTPase) [NCBI Gene 16653] {aka K-Ras, K-Ras 2, K-ras, Ki-ras, Kras-2, Kras2}, E2F1 (E2F transcription factor 1) [NCBI Gene 1869] {aka E2F-1, RBAP1, RBBP3, RBP3}, Hif1a (hypoxia inducible factor 1, alpha subunit) [NCBI Gene 15251] {aka HIF-1-alpha, HIF1-alpha, HIF1alpha, MOP1, bHLHe78}, Il4 (interleukin 4) [NCBI Gene 16189] {aka BSF-1, Il-4}, SELP (selectin P) [NCBI Gene 6403] {aka CD62, CD62P, GMP140, GRMP, LECAM3, PADGEM}, Gpx4 (glutathione peroxidase 4) [NCBI Gene 625249] {aka GPx-4, GSHPx-4, PHGPx, mtPHGPx, snGPx}, Bcl2 (B cell leukemia/lymphoma 2) [NCBI Gene 12043] {aka Bcl-2, C430015F12Rik, D630044D05Rik, D830018M01Rik}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, GOLGA7 (golgin A7) [NCBI Gene 51125] {aka GCP16, GOLGA3AP1, GOLGA7A, HSPC041}, CD47 (CD47 molecule) [NCBI Gene 961] {aka IAP, MER6, OA3}, IFI27 (interferon alpha inducible protein 27) [NCBI Gene 3429] {aka FAM14D, ISG12, ISG12A, P27}, ABCG2 (ATP binding cassette subfamily G member 2 (JR blood group)) [NCBI Gene 9429] {aka ABC15, ABCP, BCRP, BMDP, CD338, CDw338}, SELL (selectin L) [NCBI Gene 6402] {aka CD62L, LAM1, LECAM1, LEU8, LNHR, LSEL}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, ABCB1 (ATP binding cassette subfamily B member 1) [NCBI Gene 5243] {aka ABC20, CD243, CLCS, ENPAT, GP170, MDR1}, NCR3 (natural cytotoxicity triggering receptor 3) [NCBI Gene 259197] {aka 1C7, CD337, LY117, MALS, NKp30}, H3P16 (H3 histone pseudogene 16) [NCBI Gene 644914] {aka H3.6, H3F3AP6, p21}
- **Diseases:** inflammation (MESH:D007249), pancreatic ductal adenocarcinoma (MESH:D021441), injury to (MESH:D014947), prostate cancer (MESH:D011471), glioma (MESH:D005910), melanoma (MESH:D008545), bone and skin tumors (MESH:D001859), cervical cancer (MESH:D002583), pancreatic cancer (MESH:D010190), desmoplastic tumors (MESH:D058405), mitochondrial abnormalities (MESH:D028361), multidrug resistance (MESH:D018088), lung cancer (MESH:D008175), resistance (MESH:D060467), Cancer (MESH:D009369), hypoxic (MESH:D002534), carcinogenesis (MESH:D063646), ischemia (MESH:D007511), acute myeloid leukemia (MESH:D015470), cardiotoxicity (MESH:D066126), triple (MESH:C536008), Hyperthermia (MESH:D005334), non-small cell lung cancer (MESH:D002289), Hypoxia (MESH:D000860), lung metastases (MESH:D009362), reperfusion injury (MESH:D015427), leukemic (MESH:D007938), colon cancer (MESH:D015179), cytotoxic (MESH:D064420), weight loss (MESH:D015431), breast cancer (MESH:D001943), kidney impairment (MESH:D007674), negative (MESH:D064726), organ damage (MESH:D000092124), LCC-6-WT (MESH:D006528), necrosis (MESH:D009336), bladder cancer (MESH:D001749), glioblastoma (MESH:D005909), solid (MESH:D018250), brain tumor (MESH:D001932)
- **Chemicals:** epigallocatechin gallate (MESH:C045651), adenosine (MESH:D000241), Metal (MESH:D008670), Sparfloxacin (MESH:C061363), Gold (MESH:D006046), vitamin D (MESH:D014807), MCM-41 (MESH:C509968), 4,4'-azodianiline (MESH:C021143), chitosan (MESH:D048271), ferumoxytol (MESH:D052203), PI (MESH:D010716), phosphate (MESH:D010710), oxygen (MESH:D010100), Poly(ortho esters (MESH:C401107), MOFs (MESH:D000073396), polysaccharide (MESH:D011134), losartan (MESH:D019808), fucoidan (MESH:C007789), 2-nitroimidazole (MESH:C006667), azide (MESH:D001386), nitrogen (MESH:D009584), beta-cyclodextrin (MESH:C031215), paclitaxel (MESH:D017239), PEG (MESH:D011092), Trastuzumab (MESH:D000068878), nitroimidazole (MESH:D009593), Polymer (MESH:D011108), rapamycin (MESH:D020123), Carbon (MESH:D002244), polyaniline (MESH:C416807), 5-fluorouracil (MESH:D005472), hesperetin (MESH:C013015), Copper sulfide (MESH:C017846), tanshinones (MESH:C021751), copper chloride (MESH:C029892), methotrexate (MESH:D008727), coumarin (MESH:C030123), DiD (MESH:D017878), Gambogic acid (MESH:C052659), silver (MESH:D012834), DTT (MESH:D004229), Polydopamine (MESH:C568283), resveratrol (MESH:D000077185), iron oxide (MESH:C000499), Copper (MESH:D003300), artesunate (MESH:D000077332), BaTiO3 (MESH:C024547), nitric oxide (MESH:D009569), decitabine (MESH:D000077209), hyaluronan (MESH:D006820), niclosamide (MESH:D009534), 2-aminoimidazole (MESH:C014973), 5-fluorodeoxyuridine (MESH:D005467), DEC (-), Poly(glycidyl ether) (MESH:C000629095), hydrogen peroxide (MESH:D006861), IR780 (MESH:C548458), cisplatin (MESH:D002945), Conferone (MESH:C513235), H&amp;E (MESH:D006371)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Panax ginseng (Asiatic ginseng, species) [taxon 4054], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606]
- **Cell lines:** BxPC-3 — Homo sapiens (Human), Pancreatic ductal adenocarcinoma, Cancer cell line (CVCL_0186), A549 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_0023), CT26 — Mus musculus (Mouse), Mouse colon adenocarcinoma, Cancer cell line (CVCL_7254), TR146 — Homo sapiens (Human), Buccal mucosa squamous cell carcinoma, Cancer cell line (CVCL_2736), RAW 264.7 — Mus musculus (Mouse), Mouse leukemia, Cancer cell line (CVCL_0493), MCF-7 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0031), BT-549 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_1092), 4T1 — Mus musculus (Mouse), Malignant neoplasms of the mouse mammary gland, Cancer cell line (CVCL_0125), MDA-MB-231 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0062), PC9 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_B260), LCC-6-WT — Homo sapiens (Human), Laryngeal squamous cell carcinoma, Cancer cell line (CVCL_IU63), BT474 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0179), SCC-7 — Mus musculus (Mouse), Mouse squamous cell carcinoma, Cancer cell line (CVCL_V412), HeLa — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_0030)

## Figures

13 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12944085/full.md

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Source: https://tomesphere.com/paper/PMC12944085