A. Biological barriers

As shown in Fig. 1, biological barriers present a challenge for the nanocarriers to effectively convey the drug to the target site. When the therapeutic nanocarriers are loaded into the blood vessel, they first face the intravascular barrier, i.e., the mononuclear phagocyte system. The blood contains extracellular proteins referred to as opsonins forming the intravascular barrier. When the nanoparticles enter the bloodstream, these proteins quickly bind to the surface of the nanoparticles.29,3129. Q. Huang and J. Du, in New Nanomaterials and Techniques for Tumor-Targeted Systems (Springer, 2020), pp. 5–26.31. R. K. Jain and T. Stylianopoulos, Nat. Rev. Clin. Oncol. 7, 653 (2010). https://doi.org/10.1038/nrclinonc.2010.139 The opsonins make the nanocarriers more visible to macrophages, which recognize and remove the nanocarriers before they reach the tumor tissue. This biological process is known as opsonization, and it decreases the therapeutic efficacy.

Once the nanocarriers pass the intravascular barrier, they face the endothelial barrier, a semi-permeable layer of cells that line through the inner walls of the blood vessels. It prevents the extravasation of nanocarriers to the target site. For example, the endothelial layer between blood flow and the brain is highly restrictive because of the high density of endothelial cells and tight junctions between cells that prevent extravasation.

Solid tumors comprise tumor cells, stromal, extracellular matrix (ECM), vasculature, and immune cells. After crossing the endothelial barrier, the nanocarriers pass through the ECM, referred to as the extracellular barrier. The ECM comprises a collagen network, glycosaminoglycan, microfibrillar elastins, and proteoglycan, forming a cross-linked gel-like viscous structure. The viscous nature of the extracellular space or the interstitium limits the fluid flow and the diffusion of the nanocarriers from blood toward the targeted cells. ECM in the tumor microenvironment has poorly functioning vasculature, which causes high interstitial pressure.37,3837. Z. Zhang, H. Wang, T. Tan, J. Li, Z. Wang, and Y. Li, Adv. Funct. Mater. 28, 1801840 (2018). https://doi.org/10.1002/adfm.20180184038. S. Barua and S. Mitragotri, Nano Today 9, 223 (2014). https://doi.org/10.1016/j.nantod.2014.04.008 The interstitial pressure is measured between 10 and 40 mmHg for a wide range of tumor types.3939. Y. Boucher, J. M. Kirkwood, D. Opacic, M. Desantis, and R. K. Jain, Cancer Res. 51, 6691 (1991). High interstitial pressure is an essential barrier to drug delivery, especially for macromolecular drugs whose transport is mainly by convection. Finally, the nanocarriers enter the cell to release the drug into the cell membrane; therefore, the cellular barrier starts. Nanoparticles cannot simply enter the cells by diffusion. Instead, they are internalized by endocytic processes, comprising phagocytosis, pinocytosis, or endocytosis. The size, shape, and charge of nanocarriers can affect the internalization process.4040. N. Oh and J.-H. Park, Int. J. Nanomed. 9, 51 (2014). https://doi.org/10.2147/IJN.S26592

B. Types of nanocarriers

The main challenge in the clinical applications of drug-delivery systems is to overcome the biological barriers. For this purpose, the use of different types of nanocarriers is proposed. In Table I, different applications for different nanoparticle types are given, which are recently approved by the Food and Drug Administration (FDA). In this section, the types of these nanocarriers are reviewed.41–4841. X. Lin, R. Gao, Y. Zhang, N. Qi, Y. Zhang, K. Zhang, H. He, and X. Tang, Expert Opin. Drug Deliv. 9, 767 (2012). https://doi.org/10.1517/17425247.2012.68593342. B. Lasa-Saracibar, A. Estella-Hermoso de Mendoza, M. Guada, C. Dios-Vieitez, and M. J. Blanco-Prieto, Expert Opin. Drug Deliv. 9, 1245 (2012). https://doi.org/10.1517/17425247.2012.71792843. M. T. Ansari, T. A. Ramlan, N. N. Jamaluddin, N. Zamri, R. Salfi, A. Khan, F. Sami, S. Majeed, and M. S. Hasnain, Curr. Pharm. Des. 26, 4272 (2020). https://doi.org/10.2174/138161282666620072023575244. N. Avramović, B. Mandić, A. Savić-Radojević, and T. Simić, Pharmaceutics 12, 298 (2020). https://doi.org/10.3390/pharmaceutics1204029845. R. Tong and J. Cheng, J. Macromol. Sci. Polym. Rev. 47, 345 (2007). https://doi.org/10.1080/1558372070145507946. J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. Li, and Y. Xia, Nano Lett. 5, 473 (2005). https://doi.org/10.1021/nl047950t47. L. R. Hirsch, A. M. Gobin, A. R. Lowery, F. Tam, R. A. Drezek, N. J. Halas, and J. L. West, Ann. Biomed. Eng. 34, 15 (2006). https://doi.org/10.1007/s10439-005-9001-848. A. A. Yetisgin, S. Cetinel, M. Zuvin, A. Kosar, and O. Kutlu, Molecules 25, 2193 (2020). https://doi.org/10.3390/molecules25092193 As shown in Fig. 2, the most widely used drug carriers are polymeric, inorganic, and lipid-based nanocarriers.TypeDrugApplicationDate of first approvalLipid-basedOnpattroTransthyretin-mediated amyloidosis2018Polymer-basedAdynovateHemophilia2015InorganicInjectaferIron-deficiency anemia2013The first group, polymeric nanocarriers, can be synthesized from natural or synthetic materials, monomers, or preformed polymers. The main categories of polymeric nanoparticles are polymersomes, dendrimers, and nanospheres. Polymersomes are the amphiphilic block copolymer that forms the bilayer of the nanocarrier. For the first time, Zheng et al.4949. C. Zheng, L. Qiu, and K. Zhu, Polymer 50, 1173 (2009). https://doi.org/10.1016/j.polymer.2009.01.004 showed that grafted poly(phosphazenes) could be constructed into polymersomes, a new carrier for the delivery of water-soluble anti-cancer drugs. Shae et al.5050. D. Shae, K. W. Becker, P. Christov, D. S. Yun, A. K. Lytton-Jean, S. Sevimli, M. Ascano, M. Kelley, D. B. Johnson, J. M. Balko, and J. T. Wilson, Nat. Nanotechnol. 14, 269 (2019). https://doi.org/10.1038/s41565-018-0342-5 demonstrated an application of a pH-responsive polymersome to deliver a cancer vaccine. Dendrimers are another example of polymeric nanocarriers, highly branched, nanosized symmetric molecules. Nigam and Bahadur5151. S. Nigam and D. Bahadur, Colloids Surf. B 155, 182 (2017). https://doi.org/10.1016/j.colsurfb.2017.04.025 studied the fabrication and characterization of cationic and biocompatible peptide dendrimers, which stabilize and functionalize magnetite nanoparticles to treat cancer. They obtained the dimethoxyamphetamines (DOX) release profiles from the DOX-loaded dendritic nanoparticles under low pH conditions over 48 h. Their results show that a cumulative drug release is around 70% for the peptide dendrimers and 10% for the poly(amidoamine) dendrimers after 15 h.5151. S. Nigam and D. Bahadur, Colloids Surf. B 155, 182 (2017). https://doi.org/10.1016/j.colsurfb.2017.04.025 Amreddy et al.5252. N. Amreddy, A. Babu, J. Panneerselvam, A. Srivastava, R. Muralidharan, A. Chen, Y. D. Zhao, A. Munshi, and R. Ramesh, Nanomed.: Nanotechnol. Biol. Med. 14, 373 (2018). https://doi.org/10.1016/j.nano.2017.11.010 studied the effect of anti-cancer drugs on treatment of lung cancer. They functionalized dendrimers with targeting ligands to be recognized by various surface receptors, e.g., folate receptor alpha. The results show that a specially designed drug-delivery system is required to encapsulate different agents, such as a combination of small interfering RNA (siRNA) and chemotherapy for the targeted drug delivery.5252. N. Amreddy, A. Babu, J. Panneerselvam, A. Srivastava, R. Muralidharan, A. Chen, Y. D. Zhao, A. Munshi, and R. Ramesh, Nanomed.: Nanotechnol. Biol. Med. 14, 373 (2018). https://doi.org/10.1016/j.nano.2017.11.010 Another example of the polymeric nanocarrier, the nanosphere, is a polymeric matrix of a spherical shape. The drug is dissolved and encapsulated in the matrix of the polymer. Feng et al.5353. S.-S. Feng, L. Mu, K. Y. Win, and G. Huang, Curr. Med. Chem. 11, 413 (2004). https://doi.org/10.2174/0929867043455909 studied paclitaxel-loaded nanospheres, which were prepared using poly(d,l-lactic acid) and poly(d,l-lactic-co-glycolic acid) (PLGA) polymers.The second group includes inorganic nanoparticles, synthesized from metal-based materials, e.g., silica,54,5554. M. Vallet-Regí, F. Schüth, D. Lozano, M. Colilla, and M. Manzano, Chem. Soc. Rev. 51, 5365 (2022).55. S. Stephen, B. Gorain, H. Choudhury, and B. Chatterjee, Drug Deliv. Transl. Res. 12, 105 (2022). https://doi.org/10.1007/s13346-021-00935-4 quantum dot,56,5756. B. Gidwani, V. Sahu, S. S. Shukla, R. Pandey, V. Joshi, V. K. Jain, and A. Vyas, J. Drug Deliv. Sci. Technol. 61, 102308 (2021). https://doi.org/10.1016/j.jddst.2020.10230857. C. E. Probst, P. Zrazhevskiy, V. Bagalkot, and X. Gao, Adv. Drug Deliv. Rev. 65, 703 (2013). https://doi.org/10.1016/j.addr.2012.09.036 gold,5858. S. J. Amina and B. Guo, Int. J. Nanomed. 15, 9823 (2020). https://doi.org/10.2147/IJN.S279094 and iron.59,6059. R. P. Gambhir, S. S. Rohiwal, and A. P. Tiwari, Appl. Surf. Sci. 11, 100303 (2022). https://doi.org/10.1016/j.apsadv.2022.10030360. N. Maghsoudnia, R. B. Eftekhari, A. N. Sohi, A. Zamzami, and F. A. Dorkoosh, J. Nanopart. Res. 22, 245 (2020). https://doi.org/10.1007/s11051-020-04959-8 Nanoparticles are injected locally. An external field, e.g., a magnetic field, can be used to manipulate the nanoparticles. Mesoporous silica nanoparticles (MSNs) are promising nanocarriers in target-specific drug delivery due to higher intrinsic stability and biocompatibility.61,6261. A. Baeza, D. Ruiz-Molina, and M. Vallet-Regí, Expert Opin. Drug Deliv. 14, 783 (2017). https://doi.org/10.1080/17425247.2016.122929862. M. Vallet-Regi, A. Rámila, R. Del Real, and J. Pérez-Pariente, Chem. Mater. 13, 308 (2001). https://doi.org/10.1021/cm0011559 Chen et al.6363. S. Chen, S. Greasley, Z. Ong, P. Naruphontjirakul, S. Page, J. Hanna, A. Redpath, O. Tsigkou, S. Rankin, M. Ryan, A. Porter, and J. Jonesa, Mater. Today Adv. 6, 100066 (2020). https://doi.org/10.1016/j.mtadv.2020.100066 investigated zinc-doped MSNs as tunable biodegradable nanocarriers that can deliver therapeutic zinc ions inside tumor cells after internalization. Also, MSNs can be incorporated into the microspheres to increase the specific surface area, biocompatibility, and functionalization due to the Si–OH groups on the surface.6464. Y. Wang, Q. Zhao, N. Han, L. Bai, J. Li, J. Liu, E. Che, L. Hu, Q. Zhang, T. Jiang, and S. Wang, Nanomed.: Nanotechnol. Biol. Med. 11, 313 (2015). https://doi.org/10.1016/j.nano.2014.09.014 A different example of inorganic nanoparticles, quantum dots, is a semiconducting cluster of atoms prepared artificially. Quantum dots (QDs) were created by Texas Instruments, Inc. in the 1980s6565. J. Drbohlavova, V. Adam, R. Kizek, and J. Hubalek, Int. J. Mol. Sci. 10, 656 (2009). https://doi.org/10.3390/ijms10020656 and have been used in various applications, e.g., cancer diagnosis and therapy.6666. A. M. Bagher, Sens. Transducers 198, 37 (2016). QDs can be coated with hydrophilic ligands, such as thiols, thiol acids, and thiol siloxane acids,6767. J. Zhou, Y. Liu, J. Tang, and W. Tang, Mater. Today 20, 360 (2017). https://doi.org/10.1016/j.mattod.2017.02.006 or monothiol ligands, including 3-mercaptopropionic acid to improve QDs’ water solubility and biocompatibility.6868. M. Ali, D. Zayed, W. Ramadan, O. A. Kamel, M. Shehab, and S. Ebrahim, Int. Nano Lett. 9, 61 (2019). https://doi.org/10.1007/s40089-018-0262-2 Studies of chloroform-dispersed phospholipid micellar QDs in primates showed that after three months, high levels of QDs are observed in the spleen, liver, and kidney by inductively coupled mass spectrometry. However, compared with graphene nanoparticles, graphene QD is less toxic, more hydrophobic, and more stable.6969. S. Zhu, Q. Meng, L. Wang, J. Zhang, Y. Song, H. Jin, K. Zhang, H. Sun, H. Wang, and B. Yang, Angew. Chem., Int. Ed. 125, 4045 (2013). https://doi.org/10.1002/ange.201300519 Gold nanoparticles are also a good choice for biomedical applications due to their stabilization, functionalization, low toxicity, and ease of detection. Gold nanorods are irradiated with a continuous near-infrared laser at 800 nm.7070. X. Huang, I. H. El-Sayed, W. Qian, and M. A. El-Sayed, J. Am. Chem. Soc. 128, 2115 (2006). https://doi.org/10.1021/ja057254a The tumor suppression with gold nanorods is investigated in vivo.7171. G. Von Maltzahn, J.-H. Park, A. Agrawal, N. K. Bandaru, S. K. Das, M. J. Sailor, and S. N. Bhatia, Cancer Res. 69, 3892 (2009). https://doi.org/10.1158/0008-5472.CAN-08-4242 The tumors, treated with nanorods, disappeared after ten days of treatment. Ngwa et al.7272. W. Ngwa, S. Dougan, and R. Kumar, Int. J. Radiat. Oncol. Biol. Phys. 99, E611 (2017). https://doi.org/10.1016/j.ijrobp.2017.06.2073 studied the effects of gold nanoparticle-aided radiotherapy combined with antibodies on pancreatic adenocarcinoma. The tumor mass was reduced by 74%. By contrast, if the antibody was used without gold nanoparticles, tumor reduction was just 34%. Among the vast number of drug nanocarriers, magnetic iron oxide nanoparticles (IONs) differ since they can achieve high drug loading. Iron oxides are used to synthesize magnetic nanoparticles for magnetic targeting of tumor cells.73,7473. B. S. Sekhon and S. R. Kamboj, Nanotechnol. Biol. Med. 6, 516 (2010). https://doi.org/10.1016/j.nano.2010.04.00474. D. Wang, J. Zhou, R. Chen, R. Shi, G. Xia, S. Zhou, Z. Liu, N. Zhang, H. Wang, Z. Guo, and Q. Chen, Biomaterials 107, 88 (2016). https://doi.org/10.1016/j.biomaterials.2016.08.039 The large surface of porous Fe3O4 structures facilitates the delivery of drugs via surface absorption. Their release is controlled by the AC/DC field.7575. M. Mustapić, M. S. Al Hossain, J. Horvat, P. Wagner, D. R. Mitchell, J. H. Kim, and G. Alici, Microporous Mesoporous Mater. 226, 243 (2016). https://doi.org/10.1016/j.micromeso.2015.12.032 Álvarez et al.7676. E. Álvarez, M. Estévez, A. Gallo-Cordova, B. González, R. R. Castillo, M. D. P. Morales, and M. Colilla, Pharmaceutics 14, 163 (2022). https://doi.org/10.3390/pharmaceutics14010163 studied the design of a new MSN-based magnetic nanosystem to combine the triggered release of antibiotics and magnetic hyperthermia against bacterial biofilms. For this purpose, iron oxide nanoparticles are decorated with mesoporous silica.The third group, lipid-based nanocarriers, is typically spherical platforms that include a lipid bilayer surrounding the internal aqueous part. Figure 2 shows lipid-based nanocarriers: liposomes, lipid nanoparticles, emulsions, and micelles. Liposomes are spherical carriers with a vesicle shell and an aqueous core. They contain single or multiple bilayer membrane structures composed of synthetic or natural lipids. Doxorubicin is the first Food and Drug Administration (FDA)-approved nano-drug delivered with PEGylated liposomes to treat Kaposi’s sarcoma in AIDS patients.7777. N. James, R. Coker, D. Tomlinson, J. Harris, M. Gompels, A. Pinching, and J. Stewart, Clin. Oncol. 6, 294 (1994). https://doi.org/10.1016/S0936-6555(05)80269-9 As mentioned in Sec , when doxorubicin is combined with the PEGylated liposomes, the opsonization can be minimized, which increases the circulation time of the nanocarrier in blood.7777. N. James, R. Coker, D. Tomlinson, J. Harris, M. Gompels, A. Pinching, and J. Stewart, Clin. Oncol. 6, 294 (1994). https://doi.org/10.1016/S0936-6555(05)80269-9 DaunoXome and Myocet are examples of liposomes used clinically. Without PEG coating, DaunoXome and Myocet have shorter circulation times in blood.2727. D. Peer, J. M. Karp, S. Hong, O. C. Farokhzad, R. Margalit, and R. Langer, Nat. Nanotechnol. 2, 751 (2007). https://doi.org/10.1038/nnano.2007.387 Doxil is another liposome approved by the FDA for treating recurrent ovarian cancer78,7978. F. M. Muggia, Drugs 54, 22 (1997). https://doi.org/10.2165/00003495-199700544-0000679. Y. C. Barenholz, J. Control Release 160, 117 (2012). https://doi.org/10.1016/j.jconrel.2012.03.020 and breast cancer in the USA.7979. Y. C. Barenholz, J. Control Release 160, 117 (2012). https://doi.org/10.1016/j.jconrel.2012.03.020 Recently, pH-sensitive liposomes have been designed as nanocarriers to ensure efficient drug delivery in non-small-cell lung carcinoma (NSCLC), which is the leading cause of lung cancer-related death.8080. Y. I. Park, S.-H. Kwon, G. Lee, K. Motoyama, M. W. Kim, M. Lin, T. Niidome, J. H. Choi, and R. Lee, J. Control Release 330, 1 (2021). https://doi.org/10.1016/j.jconrel.2020.12.011 Another type of lipid-based nanocarriers is lipid nanoparticles. They have liposome-like structures and are widely used to deliver nucleic acids. The difference between the lipid nanoparticles and the liposomes is the micellar structures in the particle core of the lipid nanoparticles. The third group is the nanoemulsion system. Nanoemulsions can be used to prepare nanocarriers for entrapping the drug. Mendes et al.8181. S. Mendes, S. Graziani, T. Vitório, A. Padoveze, R. Hegg, S. Bydlowski, and R. Maranhão, Gynecol. Oncol. 112, 400 (2009). https://doi.org/10.1016/j.ygyno.2008.10.018 showed that the injection of the lipid nanoemulsion concentrates the nanocarrier in breast carcinoma. Hence, nanoemulsions can be a promising way of drug targeting for breast cancer treatment. Rapport et al.82,8382. N. Rapoport, Z. Gao, and A. Kennedy, J. Natl. Cancer Inst. 99, 1095 (2007). https://doi.org/10.1093/jnci/djm04383. N. Rapoport, K.-H. Nam, R. Gupta, Z. Gao, P. Mohan, A. Payne, N. Todd, X. Liu, T. Kim, J. Shea, C. Scaife, D. L. Parker, F.-K. Jeong, and A. M. Kennedy, J. Control. Release 153, 4 (2011). https://doi.org/10.1016/j.jconrel.2011.01.022 studied nanoemulsions containing anti-cancer drugs. Emulsions undergo a droplet-to-bubble transition under the effect of ultrasound. The emulsion can selectively release the drug. What’s more, the bubbles provide enhanced contrast at the tumor site. However, using perfluoropentane can be challenging due to its low boiling point.8282. N. Rapoport, Z. Gao, and A. Kennedy, J. Natl. Cancer Inst. 99, 1095 (2007). https://doi.org/10.1093/jnci/djm043 Lipid-based micelles are another example of this group. The first report on lipid-based micelles for cancer treatment is by Gao et al.,8484. Z. Gao, A. N. Lukyanov, A. Singhal, and V. P. Torchilin, Nano Lett. 2, 979 (2002). https://doi.org/10.1021/nl025604a who demonstrated that the poly(ethylene glycol)-diacyl lipid micelles show enhanced accumulation in tumors in mice. The results show that after 48 h of incubation, the micelles retained 95% of m-porphyrin, 75% of tamoxifen, and 87% of taxol. Therefore, the drug associated with these micelles is highly stable.Various inorganic nanoparticles (e.g., gold, silver, platinum, zinc oxide, iron oxide, and cerium oxide) have been successfully prepared and employed in clinical studies. Lipid-based nanocarriers have been widely used as drug-delivery vehicles because of their charge, versatile size, and surface properties.7272. W. Ngwa, S. Dougan, and R. Kumar, Int. J. Radiat. Oncol. Biol. Phys. 99, E611 (2017). https://doi.org/10.1016/j.ijrobp.2017.06.2073 Most inorganic nanoparticles have good biocompatibility and stability. However, their clinical use is limited due to toxicity concerns, especially in formulations using heavy metals. Due to these concerns, polymeric nanoparticles are preferred over inorganic nanoparticles. Polymeric nanoparticles offer reduced systemic toxicity and high biodegradability and biocompatibility.35,8735. M. J. Mitchell, M. M. Billingsley, R. M. Haley, M. E. Wechsler, N. A. Peppas, and R. Langer, Nat. 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C. Targeting strategies

As mentioned in Sec. , nanocarriers face different biological barriers when injected into the body. Various strategies are used to overcome these biological barriers to improve the accumulation and retention of the nanocarriers in the targeted area. There are currently three types of targeting strategies. The first one is the passive targeted drug delivery, known as the enhanced permeability and retention effect (EPR-effect). The second one, active targeted drug delivery, includes the delivery systems conjugated with a specific ligand. In the third one, active triggered targeting, an external field or physical stimuli, is applied to the target area to increase drug accumulation (Fig. 3).Nanoparticles, generally bigger than 10 nm, cannot cross healthy vessels through the continuous endothelium cells. However, the endothelial cells become more permeable under different pathological states, such as inflammation, infarcts, and the development of tumors. This phenomenon is named the EPR-effect.88–9088. Y. Matsumura and H. Maeda, Cancer Res. 46, 6387 (1986).89. J. Fang, H. Nakamura, and H. Maeda, Adv. Drug Deliv. Rev. 63, 136 (2011). https://doi.org/10.1016/j.addr.2010.04.00990. A. K. Iyer, G. Khaled, J. Fang, and H. Maeda, Drug Discov. Today 11, 812 (2006). https://doi.org/10.1016/j.drudis.2006.07.005 Molecules of certain sizes, e.g., nanoparticles, liposomes, and macromolecular drugs, accumulate in tumor tissues more than in normal tissues due to the EPR effect. This targeting type is referred to as passive targeting, whose success is related to the circulation time of the nanocarrier in blood. The charge of the nanoparticles affects the stability and distribution of the nanoparticles in blood. For example, positively charged nanoparticles are more stable in blood; however, after extravasation of nanoparticles from tumor vessels, neutral nanoparticles diffuse better through tissue.91–9391. C. R. Miller, B. Bondurant, S. D. McLean, K. A. McGovern, and D. F. O’Brien, Biochemistry 37, 12875 (1998). https://doi.org/10.1021/bi980096y92. S. E. Gratton, P. A. Ropp, P. D. Pohlhaus, J. C. Luft, V. J. Madden, M. E. Napier, and J. M. DeSimone, Proc. Natl. Acad. Sci. U.S.A. 105, 11613 (2008). https://doi.org/10.1073/pnas.080176310593. T. Osaka, T. Nakanishi, S. Shanmugam, S. Takahama, and H. Zhang, Colloids Surf. B 71, 325 (2009). https://doi.org/10.1016/j.colsurfb.2009.03.004 The charge-conversion strategies aim to switch the charge of nanoparticles at the target site in response to environmental stimuli, e.g., the pH of the site.9494. Y. Lee, S. Fukushima, Y. Bae, S. Hiki, T. Ishii, and K. Kataoka, J. Am. Chem. Soc. 129, 5362 (2007). https://doi.org/10.1021/ja071090b Yuan et al.9595. Y.-Y. Yuan, C.-Q. Mao, X.-J. Du, J.-Z. Du, F. Wang, and J. Wang, Adv. Mater. 24, 5476 (2012). https://doi.org/10.1002/adma.201202296 obtained zwitterionic nanoparticles containing doxorubicin, which can prolong the circulation time of nanoparticles in blood. Upon extravasation of nanoparticles into tumor microenvironments with pH values of around 6.8, the anionic component of the surface is changed to a positive surface charge. Furthermore, the nanoparticles’ shape and coating material affect the effectiveness of passive targeting. The best cellular uptake is obtained by rods, followed by spheres, cylinders, and cubes.92,9692. S. E. Gratton, P. A. Ropp, P. D. Pohlhaus, J. C. Luft, V. J. Madden, M. E. Napier, and J. M. DeSimone, Proc. Natl. Acad. Sci. U.S.A. 105, 11613 (2008). https://doi.org/10.1073/pnas.080176310596. A. Albanese, P. S. Tang, and W. C. Chan, Annu. Rev. Biomed. Eng. 14, 1 (2012). https://doi.org/10.1146/annurev-bioeng-071811-150124 Parveen and Sahoo9797. S. Parveen and S. K. Sahoo, Eur. J. Pharmacol. 670, 372 (2011). https://doi.org/10.1016/j.ejphar.2011.09.023 determined that coating PLGA nanoparticles with poloxamer 188 shows a decrease in macrophages.9898. D. Jain, R. Athawale, A. Bajaj, S. Shrikhande, P. N. Goel, and R. P. Gude, Colloids Surf. B 109, 59 (2013). https://doi.org/10.1016/j.colsurfb.2013.03.027The second method, active targeting, is achieved by a conjugated ligand on the surface of the nanoparticles. The active targeting mechanism relies on the interaction between the ligand of the nanoparticle and the cell surface receptors or the antigens on the tumor cell’s surface. Active targeting of the drug-loaded nanocarriers overcomes the drawbacks of passive targeting by making the nanoparticle more specific to a target site. Consequently, active targeting results in higher drug accumulation increases in the tumor cells, reducing chemotherapeutic treatments’ side effects9999. R. Bazak, M. Houri, S. El Achy, S. Kamel, and T. Refaat, J. Cancer Res. Clin. Oncol. 141, 769 (2015). https://doi.org/10.1007/s00432-014-1767-3 compared to passive targeting. Watanabe et al.100100. K. Watanabe, M. Kaneko, and Y. Maitani, Int. J. Nanomed. 7, 3679 (2012). https://doi.org/10.2147/IJN.S32853 studied folate-polymer-coated liposomes for targeted delivery of doxorubicin. Their results show that doxorubicin-loaded folic acid conjugated with liposomes exhibited twofold higher cytotoxicity. Rana et al.101101. S. Rana, N. G. Shetake, K. Barick, B. Pandey, H. Salunke, and P. Hassan, Dalton Trans. 45, 17401 (2016). https://doi.org/10.1039/C6DT03323G developed Fe3O4 magnetic nanoparticles conjugated with folic acid to deliver doxorubicin. They found that the accumulation of drugs in the tumor cells increases about threefold. Transferrin is another example of a ligand, which is a blood plasma glycoprotein. Sahoo and Labhasetwar102102. S. K. Sahoo and V. Labhasetwar, Mol. Pharm. 2, 373 (2005). https://doi.org/10.1021/mp050032z demonstrated that transferrin ligand conjugated poly(lactic-coglycolide) nanoparticles enhance efficacy in breast cancer cells. Yang et al.103103. H. Yang, C. Tang, and C. Yin, Acta Biomater. 73, 400 (2018). https://doi.org/10.1016/j.actbio.2018.04.020 demonstrated the synthesis of estrone-modified glycol chitosan nanoparticles for drug (PTX) delivery. PTX-loaded chitosan nanoparticles show higher drug (PTX) accumulation (81.4%) than the pure drug PTX (48.8%) in mice breast cancer cells. Recently, Cadinoiu et al.1616. A. N. Cadinoiu, D. M. Rata, L. I. Atanase, C. T. Mihai, S. E. Bacaita, and M. Popa, Pharmaceutics 13, 866 (2021). https://doi.org/10.3390/pharmaceutics13060866 studied the preparation of liposomes with an aptamer ligand to treat basal cell carcinoma. The over-expression of the biotin receptor is approximately 40 times higher in hepatocellular carcinoma cells than in normal liver cells.The final approach for drug targeting strategies is active triggering.105–107105. S. Mura, J. Nicolas, and P. Couvreur, Nat. Mater. 12, 991 (2013). https://doi.org/10.1038/nmat3776106. V. P. Torchilin, Nat. Rev. Drug Discov. 13, 813 (2014). https://doi.org/10.1038/nrd4333107. P. Bawa, V. Pillay, Y. E. Choonara, and L. C. Du Toit, Biomed. Mater. 4, 022001 (2009). https://doi.org/10.1088/1748-6041/4/2/022001 Triggers are internal, e.g., variations in pH at different microenvironments or external, e.g., temperature, ultrasound, magnetic field, and ultraviolet/near-infrared radiation.105105. S. Mura, J. Nicolas, and P. Couvreur, Nat. Mater. 12, 991 (2013). https://doi.org/10.1038/nmat3776 Nanocarriers can be designed to respond to these stimuli and achieve an enhanced drug release in a precise location. It is known that the tumor microenvironment is quite different from normal tissues, e.g., different expression levels of some enzymes and its acidic environment108–110108. M. Shahriari, M. Zahiri, K. Abnous, S. M. Taghdisi, M. Ramezani, and M. Alibolandi, J. Control. Release 308, 172 (2019). https://doi.org/10.1016/j.jconrel.2019.07.004109. Z. Cao, W. Li, R. Liu, X. Li, H. Li, L. Liu, Y. Chen, C. Lv, and Y. Liu, Biomed. Pharmacother. 118, 109340 (2019). https://doi.org/10.1016/j.biopha.2019.109340110. Q. Hu, P. S. Katti, and Z. Gu, Nanoscale 6, 12273 (2014). https://doi.org/10.1039/C4NR04249B and pH values. The pH value in tumor tissues is lower than in blood and normal tissues (7.4), and the acidic cellular environments exhibit even lower values, e.g., 4.5–5.0 for lysosomes and 5.5–6.0 for endosomes.111111. Q. Yang, S. Wang, P. Fan, L. Wang, Y. Di, K. Lin, and F.-S. Xiao, Chem. 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The drug concentration is analyzed using UV spectrophotometry. The results show that the drug release rates are significantly accelerated when the pH of the environment is changed from 7.4 to 5.0. Zhao et al.114114. H. Zhao, H. H. P. Duong, and L. Y. L. Yung, Macromol. Rapid Commun. 31, 1163 (2010). https://doi.org/10.1002/marc.200900876 showed that the micelles exhibit excellent anti-tumor efficacy with folate-mediated cancer targeting and pH-triggered intracellular drug delivery. The drug loading contents of 20:80 (20% β-amino ester in the mixed micelles), 50:50, and 80:20 mixed micelles and pure micelles are studied. Compared to pure micelles, the 20:80 mixed micelles show decreased drug release at pH 7.4. Drug release can also be governed by an increase in the temperature of the tumor environment. The stimulus may be extrinsic or intrinsic, which provides hyperthermia. The local application of heat, ultrasound, or light is examples of extrinsic stimuli. 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The tumor size is decreased in various animal studies, including small animals, such as rabbits and rats,127,128127. C. Alexiou, W. Arnold, R. J. Klein, F. G. Parak, P. Hulin, C. Bergemann, W. Erhardt, S. Wagenpfeil, and A. S. Luebbe, Cancer Res. 60, 6641 (2000).128. S. K. Pulfer, S. L. Ciccotto, and J. M. Gallo, J. Neuro-Oncol. 41, 99 (1999). https://doi.org/10.1023/A:1006137523591 and larger animals, such as swine.129129. S. Goodwin, C. Peterson, C. Hoh, and C. Bittner, J. Magn. Magn. Mater. 194, 132 (1999). https://doi.org/10.1016/S0304-8853(98)00584-8 The target depth extends to approximately 10 cm. Alexiou et al.130130. C. Alexiou, R. Jurgons, R. Schmid, A. Hilpert, C. Bergemann, F. Parak, and H. Iro, J. Magn. Mater. 293, 389 (2005). https://doi.org/10.1016/j.jmmm.2005.02.036 quantified the distribution of the magnetically targeted carriers in a rabbit using high-performance liquid chromatography (HPLC). The results show that complete tumor reduction with fewer chemotherapeutic doses (20% and 50% of the regular systemic dose of 10 mg/m2) are achieved without adverse effects.Among other external fields mentioned earlier, light is a promising tool for therapeutic applications due to its ease of application and noninvasive nature. As a result, light is extensively applied in targeted drug-delivery systems for the systemic delivery of therapeutic compounds. For the detailed literature review on light-triggered drug delivery, the reader is referred to Refs. 131131. Y. Tao, H. F. Chan, B. Shi, M. Li, and K. W. Leong, Adv. Funct. Mater. 30, 2005029 (2020). https://doi.org/10.1002/adfm.202005029 and 132132. T. L. Rapp and C. A. DeForest, Adv. Drug Deliv. Rev. 171, 94 (2021). https://doi.org/10.1016/j.addr.2021.01.009. In Table II, the advantages and disadvantages of different triggered targeting methods are shown.