INTRODUCTION:

Cancer poses a massive global health challenge, continually affecting individuals, families, and communities around the world¹. Nowadays, radiation is one of the common methods of clinical cancer treatment, but the resistance of cancer cells to radiotherapy is also a headache. If the radiation dose is increased to eradicate cancer cells, it will inevitably cause certain damage to normal tissues, or there are obvious side effects, so combination therapy is a trade-off that can reduce the radiation dose without affecting the efficacy^2,3. It can overcome the problem of tumor resistance by increasing the radiation sensitivity of cancer cells. Breast cancer is the most common cancer among modern women. Many clinical drugs have severe side effects and have high recurrence and metastasis rates. Among them, triple-negative breast cancer (TNBC) is the most difficult to treat and the most likely to relapse⁴. Type of breast cancer, so a breakthrough in the treatment of TNBC is also necessary. In recent years, nanomaterials technology for medical applications has become increasingly mature. Because the size range of nanoparticles is comparable to that of biomolecules and cellular systems, coupled with their unique physical and chemical properties, they can be used as effective materials for therapeutic and diagnostic applications. Precision medicine, also known as personalized medicine, seeks to provide treatments tailored to the patient's specific needs, taking into account genetic variation, environmental factors, and customary practices⁵. Precision medicine aims to clarify the molecular complexities of disease etiology and improve the identification of optimal treatment modalities that maximize efficacy while minimizing adverse effects⁶. Precision medicine has the potential to revolutionize the way cancer medicine is delivered by facilitating the delivery of drugs targeted at specific biological pathways that affect tumor growth and survival⁷.

Characteristics and applications of nanomaterials:

Nanotechnology is the science of engineering material systems at the molecular scale. Its application in medicine is called nanomedicine technology. Currently, nanoparticle drug delivery is developing rapidly⁷. These nanomedicine carriers are generally less than 100 nanometers in size and can carry and deliver therapeutic drugs to the diseased site, preferentially accumulating at the tumor site through enhanced permeability and retention (EPR). Traditional chemotherapy drugs are distributed throughout the body, affecting both cancer cells and normal cells. This difference in distribution within the body allows nanoparticles-based chemotherapy drugs to achieve higher intra-tumor efficacy than their corresponding small-molecule counterparts. concentrations and lower normal tissue concentrations. This difference can also translate into higher efficacy and lower toxicity of nanoparticle therapies, such as pegylated liposomal doxorubicin (pegylated liposomal doxorubicin), which has a lower dose limit than doxorubicin.

Several nanoparticle anti-cancer drugs have received clinical approval, while additional experimental drugs are in the process of clinical and preclinical development. These nanoparticle medications will substantially influence the management of tumor-related diseases. In the review research report by Andrew et al. (2012), different nanoparticle platforms for delivering cancer drugs will be talked about, clinical data on nanoparticle cancer drugs that are already approved will be looked at, and the clinical parts of developing nanoparticle anticancer drugs will be briefly talked about. and preliminary data, along with the prospective advancement of nanomedicines for tumor therapy⁷. To get better results, nanoparticles usually have their surfaces changed in some way. For example, markers can be added to make it easier to distinguish tumor cells from normal cells, or polymers such as chitosan, PLGA, and PEG can be used to improve biocompatibility and stability, allowing them to be evenly distributed without clumping. Nanomaterials can penetrate cells via diffusion or endocytosis facilitated by caveolae, clathrin-coated pits, and lipid rafts, owing to their unique physical and chemical characteristics. in cellular organelles, including mitochondria and lysosomes^.7,8. Nanocarriers can also effectively encapsulate different kinds of small molecules that have different physical and chemical properties and get into cells through the pathways described above. Nano has two properties that make it great for treating tumors: it can easily pass through cells and stay there for a long time (EPR), and it can attach markers. EPR is a big molecule that can get into tumor tissue more easily and stay there for a long time. Because tumors need more nutrients, they release vascular endothelial growth factors to help blood vessels grow back. This makes the spaces around the tumor cells smaller and the tumor blood vessels bigger than normal blood vessels. Tumor blood vessel walls often don't have smooth muscle, which makes new blood vessels leaky. The tumor also doesn't have lymphatic vessels, which makes it hard for lymph fluid to flow back. This means that drugs or other substances stay in the cancer tissue for longer because they can't be carried away by the return flow of lymph fluid. We can also improve the specificity to certain tissues by changing the physical properties of nanometers, such as surface potential, particle size, hydrophobicity, and so on. This allows us to attach specific and highly expressed proteins from target cells to the nanometer surface or receptors, giving us specific targeting capabilities that can let a larger proportion of substances enter cancer tissues⁹.

Nanotechnology has opened up new doors for the field of precision cancer therapy. The systemic adverse effects commonly associated with conventional pharmacological therapy are mitigated, as nanoparticles may enhance the delivery of typically insoluble medications to both proximal and distal tumor sites. These nanodrugs are always biocompatible, non-immunogenic, non-toxic, and biodegradable. This means that they are less likely to have unexpected side effects or lose their effectiveness than regular treatments. Nanomedicine, which uses nanotechnology for medical purposes, has unique benefits for accurately and effectively delivering therapeutic drugs to tumor tissues^10,11.

Common Nano-drug Delivery Platforms Nanotechnology is a relatively new field of study, but new nano-drug delivery platforms have been made as early as thirty years ago. These platforms are usually split into these groups: liposomes, nanoparticle albumin binding (nab) technology, polymeric nanoparticles (polymeric nanoparticles), dendrimers (dendrimers), metal nanoparticles (metal nanoparticles), and molecular targeted nanoparticles (molecular targeted nanoparticles). Liposomes have been the first nanoparticles used in pharmaceutical platforms since 1965. There are now more than ten liposome preparations that have been approved for clinical use, and there are more experimental drugs in clinical and preclinical development¹². Liposomes are round vesicles with a hydrophilic core and a vesicle shell¹³. They have more than one layer of bilayer membrane structure made up of natural or synthetic lipids. Depending on how they are made, they can be as small as tens of nanometers^14-16. Liposomes are good drug carriers because they are biocompatible and biodegradable, have an aqueous core covered in hydrophilic substances, and have a lamellar structure (lamellae) that contains hydrophobic substances. You can also coat micro liposomes with polyethylene glycol (PEG) polymer to make them more stable and help them stay in the blood longer. Liposome pharmaceutical dosage forms typically enhance the pharmacokinetics and biodistribution of drugs¹⁷. For instance, PEGylated liposome doxorubicin can limit the distribution of daunomycin in the plasma, which lowers its distribution volume^18–22. The body distribution volume of the free drug form is about 1,000 liters/m2, but the liposome only has 2.8 liters/m2. It can also raise the levels of drugs in tumor tissues while lowering the levels of drugs in normal tissues, like the heart. Nonetheless, considerable obstacles persist, such as the translation of preclinical results into clinical application, the creation of scalable manufacturing methodologies, and the enhancement of nanoparticle pharmacokinetics and biodistribution²³. To overcome these obstacles, interdisciplinary collaboration and continuous innovation will be essential; however, the prospective advantages for patients are significant and undeniable²⁴ see figure 1.

Methods:

For this review article, an extensive literature search was performed utilizing electronic databases including PubMed, Web of Science, and Scopus. The search terms encompassed "targeted nanomedicine," "precision cancer therapy," "nanoparticle drug delivery," and associated keywords. The review included studies that were published in peer-reviewed journals up to January 2024 and were relevant. The chosen articles underwent a critical evaluation to derive essential findings and insights regarding targeted nanomedicine strategies for cancer treatment²⁵.

Figure 1. Illustration of the characteristics and applications of nanomaterials in cancer therapy, showing the difference between traditional chemotherapy and nanoparticle-based drug delivery. Nanoparticles carrying therapeutic agents preferentially accumulate at tumor sites through the enhanced permeability and retention (EPR) effect, enabling targeted delivery, higher intratumoral concentration, and reduced systemic toxicity.

RESULTS:

Core Nanocarrier Platforms:

Over the last two decades, various strategies have been developed to fabricate a diversity of nanostructures that integrate the expected characteristics exploited in nano-carrier platforms. The general objective is generally achieved by devising novel lipid- or polymer- based nanoparticle (NP) systems, inorganic metal-based materials, or hybrid biomimetic nanostructures formed by the combination of different platforms. These progress in the nanomaterial design have enabled the delivery of cancer treatment payloads that combine different therapeutic modalities (chemo-, photothermal, photodynamic, or gene therapy) to improve therapeutic efficacy and overcome drug resistance mechanisms. Surveillance stimulation of the immune system by encapsulating immunomodulatory agents in targeted NPs further extends the anti-tumor effects. All payload modalities are designed to fulfill specific therapeutic needs that surmount the pharmacological limitations of the isolated agents²⁷.

Lipid-Based Nanoparticles:

Liposomes are the first nanocarrier systems that have entered clinical use. Their structure is analogous to that of biological membranes, and as such, they exhibit a high tolerance to biological systems. They can encapsulate hydrophilic molecules readily in their aqueous core, whereas hydrophobic agents can easily be incorporated into the lipid bilayer. In addition to conventional liposomes, other variants, including immunoliposomes, stealth liposomes, and cationic liposomes, can also enhance therapeutic efficacy. Lipid nanoparticles are now one of the famous self-assembled nano drug delivery systems. Their construction is straightforward. Natural lipids are mixed with surfactants and then assembled through the method of solvent evaporation. Lipid particles can encapsulate both lipophilic and hydrophilic drugs simultaneously in their core and shell. With the rapid development of lipid biological technology, lipid particles based on phospholipid bilayers can be employed for nucleic acid drug delivery to enhance the targeting effect in vivo. cationic lipoplexes with DNA or siRNA are used to improve RNA bioavailability.

The prey effect due to inflammed tumor vessels allows nanoparticles with mean diameters around 50 nm to penetrate tumors preferentially via passive targeting mechanism. In addition, stealth liposomes by hydrocoiling the lipid surface with PEG prolong the blood circulation time and ameliorate the toxicity in major organs. Active tumor targeting can also be achieved by conjugating antibodies or tumor-targeting peptides on the surfaces of liposomes. These modifications enhance selectivity and efficacy of tumor kill. Furthermore, the complexity of tumor microenvironment can be exploited for designing stimuli-responsive liposomes, which release their drug payloads directly within tumors. Improved tumor penetration and effective tumor-associated macrophage regulating are also pursued through bypassing MDSC blockade during liposomal delivery. Liposome-mediated co-delivery approaches of chemotherapeutics with small interfering RNA, mRNA, or photosensitizer components are stimuled to reinforce anticancer capability. Besides cancer therapy, liposomes function as efficient carrier systems for bases, protein-based drugs, analgesics, or anesthetics^27-29.

Polymer-Based Nanoparticles:

Polymeric nanoparticles (NPs)—including solid polymeric NPs, polymeric micelles, polymeric hybrids, and dendrimers—are versatile nanoformulations with immense potential to improve cancer therapy. They can be composed of natural or synthetic amphiphilic polymers, facilitating control over size, surface properties, and drug delivery profile. Consequently, cytotoxic drugs can be loaded into the solid core or surface adsorbed on solid polymeric NPs; incorporated into the core of polymeric micelles, or conjugated to the surface of polymeric micelles or dendrimers. Co-delivery of chemotherapeutics with adjuvants or therapeutic nucleic acids has also been demonstrated.

Solid polymeric NPs consisting of biodegradable polymers such as poly(lactide) (PLA) and poly(lactic-co-glycolic acid) (PLGA) and micelles assembled from amphiphilic block copolymers have been extensively explored owing to their excellent compatibility and capacity for nanocarrier properties. However, the relatively slow physiological degradation of PLA- or PLGA-based solid polymeric NPs may restrict therapeutic applications. Polymeric micelles assembled from hydrolysable amphiphilic di-block copolymers can be used to co-encapsulate small molecular drugs and efficient hydrophobic photosensitizers for combination treatment. Polymeric hybrids fabricated from PLGA and amphiphilic triblock polymers containing biocompatible poly(ethylene oxide) blocks are also efficient carriers for the co-delivery of a photosensitizer and a chemotherapeutic drug. Conjugates synthesized from generation 4.0 poly(amidoamine) dendrimers and a hydrophobic prodrug of a chemotherapeutic agent can also serve as nanocarriers for effective photo-chemotherapy of cancer²⁷.

Inorganic Nanoparticles:

Inorganic nanoparticles constitute an essential category of nanocarriers relevant for cancer therapy. A wide spectrum of inorganic nanomaterials encompasses metal monocrystals, metal oxides, carbon allotropes, and silicates. By virtue of their optical, magnetic, electric, and mechanical properties, and a broad surface area-to-volume ratio, they display unique features to be exploited in several biomedical applications. In organic form, they allow for simultaneous delivery of multiple therapeutic agents. or act as multimodal agents carrying different functionalities in a single platform. Through complexation with organophosphorus compounds, including paclitaxel or methotrexate, carbon nanotubes act as carriers that efficiently transfer the drugs Introna et al., 2019. A functionalized and photoactivated graphene oxide–APX combination has been endowed with antitumor effects on melanoma mouse cells. On the other hand, photothermally-induced graphene oxide-based BCL-2 silencing effectively inhibits the development of Triple-Negative Breast Cancer. Gadolinium-chelate liposomes Gd-galactosyl-bile-derivative liposomes are a bimodal MRI/photoacoustic and self-reporting system for targeted and image-guided photothermal-chemotherapy.

Silica-based nanoparticles represent an attractive class of these nanomaterials. Their intrinsic properties provide biocompatibility, tunable surface area, and high loading capacity. Amino-functionalized silica nanoparticles have been studied for the combined delivery of the antineoplastic drug doxorubicin and the proteasome-inhibitor MG132, designed for co-delivery to potentiate the anticancer effect.

Silica-coated gold nanoparticles are considered multifunctional nanocarriers for cancer diagnostic and therapeutic applications that combine magnetic resonance imaging with photothermal therapy and loading of doxorubicin to treat tumors. Silica and gold nanoparticles coated with doxorubicin-encapsulated nanomicelles have been used as promising drug delivery systems for cancer therapy²⁸.

Biomimetic and Hybrid Systems:

Despite the significant progress achieved with drug-based nanocarriers in preclinical settings, translation into clinical use has frequently taken longer than anticipated. For some, these delays are attributed to shortcomings in selected core materials or payloads, as well as inadequate consideration of user-associated and regulatory perspectives. These cons must be addressed to facilitate clinical translation of at least some nanomedicines and nanoprobes. One potential avenue is the use of drug-free biomimetic nanoparticles. Such systems benefit from compositionally and dimensionally similar structures to normal or diseased cells and viruses, thereby minimizing unwanted immunogenicity and accelerating blood-clearance pathways. An alternative is the elaboration of hybrid materials that incorporate biomimetic components in lipid-, polymer-, or inorganic-based nanocarriers. Also, new methods for modifying surfaces, like click chemistry and bioconjugation strategies, have made it possible to precisely control the properties of nanoparticle surfaces and the density of ligands²⁹.

Targeting Strategies to Achieve Specificity:

Targeting approaches confer the ability to direct delivery systems towards specific tumor cells while minimizing off-target effects. Three main targeting strategies have emerged: passive targeting, which exploits the enhanced permeability and retention (EPR) effect; active targeting, which directs delivery systems to specific cells via ligand–receptor or receptor–drug binding; and stimulus-responsive delivery, where the system is activated by intrinsic or extrinsic tumor properties³⁰.

Passive Targeting via Enhanced Permeability and Retention Effect:

Targeting strategies play a defining role in nanomedicine and precision oncology, yet they are often considered within a single category, namely enhanced permeability and retention (EPR) effect. Passive targeting exploits the pathophysiological characteristics of tumors, which become more porous than surrounding normal tissues, and thus can facilitate the accumulation of systemically administered nanocarrier-based formulations. Nanomedicine, however, has no intention of replacing traditional chemotherapy; rather, its underlying rationale is to achieve an optimal therapeutic efficacy-to-toxicity ratio when treating cancer patients. This approach not only utilizes the EPR effect but also explores active targeting ptions for cancer and tumor microenvironment-specific delivery. Here critical targeting strategies are presented together with representative examples illustrating their capabilities to improve the efficacy and safety of various therapeutic payload modalities³¹. The EPR effect is attributable to two major characteristics of the tumor vasculature: (1) The poorly organized endothelial cells of the tumor blood vessels have large interendothelial pores, which are absent from pre-existing, mature capillaries, and (2) the lack of an effective lymphatic drainage system allows for the accumulation of macromolecules. Evidence for EPR-based passive targeting was first observed in preclinical studies with nanoparticles, and its impact on therapeutic efficacy was confirmed using capable liposome formulations. Further positioning of the liposomal formulations for clinical translation corroborated the original findings: A 2023 Phase I trial demonstrated a clinical benefit for patients with platinum-refractory/recurrent ovarian cancer treated with RS-812 liposomes, a pegylated liposomal amphotericin B formulation; more patients experienced progression-free survival and overall survival than in clinical trials with other conventional therapies. Further support for the EPR effect in lipid-based nanocarriers has been provided by both clinical trials and animal studies with OncoTICE and Marqibo³².

Active Targeting through Ligand–Receptor Interactions:

Active targeting seeks enhanced specificity through ligand–receptor (or ligand–antigen) interactions: suitable ligands are attached to nanocarriers to redirect drug delivery to cells overexpressing the receptors. Ligands having particular prospects include transferrin, folic acid, tumor necrosis factor-α, and glycyrrhizin; with autoimmune-related receptors for rheumatoid arthritis and psoriatic arthritis; tumor antigens such as carcinoembryonic antigen; and integrin αvβ3, which is overexpressed in various cancers³². Hyaluronic acid has garnered attention, as it targets the cluster of differentiation (CD)44 receptor, known to be overexpressed in tumor cells of many solid tumors. CD44+ gastric cancer cell-targeted hybrid nanosystems have combined the chemotherapeutic agent doxorubicin with a photosensitizer and photosensitizer-loaded liposomes. Active targeting strategies can lower drug dosages and alleviate the side effects associated with conventional cancer treatments. However, low receptor affinity and ineffective ligand–receptor interactions, especially in cells with heterogeneous receptor expression, can restrict drug uptake. Stimuli-responsive carriers exploit tumor microenvironment hallmarks to facilitate selective delivery at the disease site and minimize off-target adverse effects. Acid-sensitive carriers, enabled by tumor acidity, promote endosomal escape and subsequent cytosolic release. Other stimuli-responsive carriers achieve release in response to reducing conditions, elevated enzyme levels, and specific near-infrared light irradiation³³.

Stimuli-Responsive and Environment-Sensitive Delivery:

Intelligent nanoscale carriers can release their therapeutic payloads in response to specific triggers that are either intrinsic or extrinsic to the tumor tissue. Stimuli-triggered systems are of three types: (1) internal stimuli systems, which make use of disparate environments within tumor tissues, (2) external stimuli systems, in which therapeutic agents are released in response to externally applied comprehensive signal, and (3) hybrid systems that take advantage of both internal and external signals. The unique characteristics of the TME have made it a target for cancer nanomedicine and the basis for developing a new family of “intelligent” drug-delivery systems. A number of physiological and anatomical features of the TME are especially useful for the development of intelligent drug-delivery systems: an acidic extracellular milieu, elevated levels of specific enzymes (e.g., matrix metalloproteinases, hyaluronidase) in certain tumoral tissues, and elevated levels of reductive species such as glutathione. The carefully orchestrated interplay between these signals and the nanocarriers allows triggering of therapeutic payloads at the tumor site while minimizing side effects to normal tissues³⁴.

Payload Modalities for Precision Therapy:

Chemotherapeutic drugs and their combinations, nucleic acids for gene silencing or expression, photosensitizers and photothermal agents, and immunomodulatory biomolecules are the most extensively explored payloads for inclusion in targeted nanomedicine systems. A sound selection of the specific type of payload delivered to the tumor region may result in high therapeutic efficacy under a precision medicine paradigm. High concentrations of anticancer drugs at the tumor site can potentially minimize unwanted side effects elicited by long-term systemic administration and enable drug cocktails that surpass the maximal tolerated dose proposed for the individual molecules. Gene silencing through small interfering RNA (siRNA) delivered by carriers targeting tumor cells or their microenvironment is emerging as a new axis in precision nanomedicine. On the other hand, photothermal agents respond to radiation with heat on a subcellular scale and are synergistically combined with nearby anticancer photodynamic agents. Safe and tunable delivery of immunity-boosting cytokines to the site of action represents a very promising approach for the treatment of tumors that escape immunological surveillance³⁵.

The local delivery of chemotherapeutics to the solid tumor site is expected to increase safety and tolerability, thus allowing higher effective doses than those achievable by systemic administration. Associating multiple drugs with different mechanisms of action within the same carrier may surpass the individual maximum tolerated doses and boost anticancer efficacy. Co-delivery also circumvents compensatory mechanisms triggered by monotherapy. Targeted poly(ethylene glycol) (PEG)-lipid micelles co-sheltering paclitaxel and doxorubicin demonstrated enhanced therapeutic potency in a multidrug-resistant (MDR) tumor-bearing murine model relative to either drug given separately³⁶.

Moreover, current research in targeted nanomedicine is increasingly concentrating on comprehending and surmounting obstacles to effective drug delivery in solid tumors. Nanoparticles encounter significant challenges in penetrating and disseminating within the tumor microenvironment due to tumor heterogeneity, interstitial fluid pressure, and the dense extracellular matrix. To enhance nanoparticle delivery and therapeutic response, researchers have investigated strategies such as vascular normalization, which entails administering angiogenesis inhibitors to restore tumor blood vessel functionality. Additionally, innovative nanomedicine formulations, incorporating size- and shape-controlled nanoparticles, have been developed to improve tumor infiltration and distribution, thereby increasing therapeutic efficacy.

Targeted nanomedicine research right now shows how cancer treatment can involve many different fields, including nanotechnology, molecular biology, and translational medicine. By combining new ways to make nanoparticles, targeting strategies, and tumor biology, scientists are on the verge of solving long-standing problems in cancer treatment and starting a new era of precision medicine. Targeted nanomedicine could change how cancer is treated and improve patients' lives in the future, but only if people keep coming up with new ideas and working together³⁸.

Hemotherapeutics and Drug Combinations:

Monotherapy using a single chemotherapeutic agent remains an established therapeutic regimen for various cancer types. Nanomedicine-based therapies with well-established anticancer effects reduce the toxicity of using a single drug by specifically delivering two or more anticancer agents with different mechanisms of action to tumor cells. Doxorubicin is the most studied drug in nanomedicine, and NP formulations of combination therapies with various combinations have been designed. Several surface-modified gelatin NPs encapsulating doxorubicin and cisplatin have been prepared to treat breast cancer that had developed resistance to both drugs. A combination of paclitaxel and cisplatin with an identified synergistic effect was formulated in a dual-emulsion process using poly(ε-caprolactone). The combination of P-glycoprotein inhibitors with doxorubicin has been a favorite area of study³⁹.

Doxorubicin, topotecan, and flavopiridol were encapsulated in poly-l-lactic acid NPs bearing the mAb CLBF2 to target lung tumor. One of the first studies to achieve a combination of anticancer agents with a photosensitizer used 5-aminolevulinic acid-linked liposomes loaded with doxorubicin and porphyrin. Another approach combined different chemotherapeutics with a necrosis-inducing drug. Recently, a new paradigm using landscape NPs with physically separated compartments containing a mixture of drugs with complementary mechanisms was proposed. Currents of anticancer agents with different types of action were merged for precisely coordinated therapy⁴⁰.

Nucleic Acids and Gene Regulation:

Efforts to establish nucleic acid therapeutics, including DNA and RNA therapeutics for cancer treatment, have gained traction. Therapeutic gene transfer through expression vectors, primarily viral systems, has advanced substantially. Furthermore, non-viral methods exploiting liposomes, lipid nanoparticles, dendrimers, polymers, cationic nanomicelles, and gold nanoparticles have become essential. The idea of combining gene therapy with traditional drug therapy remains convincing, enabling potential antitumor synergetic effects. Nucleic acids can serve as therapeutic agents or as carriers for other drugs or therapeutic agents³⁹.

Although only a few nucleic acid therapeutics have reached the clinic, development is underway for complementary DNA and RNA targeting: RNA interference (RNAi) therapies and the emerging CRISPR technology. Nanocarriers are vital for the advancement of RNAi therapeutics by providing protection against premature degradation, enhancing cellular uptake, and enabling endosomal escape. The application of CRISPR technology is also limited due to delivery-related challenges. Since clustered regularly interspaced short palindromic repeats endonucleases are delivered together with their RNA guides, camouflaged carriers capable of simultaneously loading multiple components show promise for effective genome editing. Cancer immunotherapy has once again reinvigorated interest in nucleic acid therapeutics, because the delivery of DNA and RNA immunoadjuvants can modulate the immune response^,40.

Photosensitizers and Photothermal Agents:

In addition to chemotherapy, the potential of two other treatment modalities is growing in the context of nanomedicine and precision oncology: photodynamic therapy (PDT) and photothermal therapy (PTT). Reactive oxygen species generated from the excitation of spatially confined proper photosensitizers lead to localized tumor ablation in PDT. The well-known limitations of photosensitizer-based systems, which lead to poor clinical outcomes, include (i) impaired tumor-specific accumulation, (ii) rapid elimination from the body, (iii) generation of oxygen deficit in the TME, (iv) limited availability of both single and multiple wavelength activation of the available PSs, and (v) poor penetration depth of visible light. Nanocarriers may help overcome these limitations by: (i) extending the pharmacokinetic profile of the cargo PSs leading to elevated tumor accumulation and reduced systemic toxicity; (ii) enabling the co-delivery of PSs together with oxygen donors, such as catalytic units for endogenous H2O2 consumption or microbubble systems that can be converted into oxygen during PDT. Recently, combining nanocarriers with newly designed PSs that can be activated from the NIR region are gaining traction, since NIR light can penetrate deeper into the tissues than visible light. Collectively, encompassing these current advances are recent reviews with a strong focus on hypoxia-free and tumor-vascular-targeted nano-PDT approaches.⁴¹

Immunomodulatory Payloads:

Nanoparticles engineered to be loaded with immunotherapeutics offer promising alternatives to restore an effective antitumoral immune response. Diverse immune-related molecules have been investigated for delivery to tumors with a focus on activating immune responses, inhibiting immune inhibition and targeting tumor-associated macrophages (TAM)⁴².

Nanoparticles loaded with toll-like receptor (TLR) agonists (imbalance of TLRs in the tumor microenvironment can promote tumor growth and metastasis) or anti-programmed death-ligand 1 antibodies have been used as adjuvants for dendritic cell (DC) vaccines⁴³. TLR7/8 agonist-bearing polymeric nanoparticles have been shown to effectively induce a localized and systemic antitumor immune response, rendering them suitable for adjuvant therapy in immunologically cold tumors and inhibiting lung metastasis^44-50. A nanoformulation combining irradiation and administration of a TLR9 agonist limits lung metastasis in a heterotopic murine model of breast cancer via the induction of a systemic immune response. Diphtheria toxin-loaded nanocarriers have demonstrated inhibition of lymph node and lung metastasis in a murine neuroblastoma model through suppression of normal tissue-resident TAM. NCs that deliver CCL2 (involved in recruitment of TAM) and a TLR7 agonist have been used to target TAM and enhance the therapeutic efficacy of a HER2 CAR-T cell therapy for HER2-positive tumors. Moreover, the delivery of fibronectin and TGF-β inhibitors into macropinosomes of TAM exploits tumor metabolism and alleviates immunosuppression by switching pro-tumor M2‐like polarization into anti-tumor M1‐like polarization^51-55.

Challenges and Future Prospects:

However, challenges loom on the path to clinical translation. Bridging the gap between bench and bedside requires surmounting hurdles of scalability, reproducibility, and regulatory approval⁴². Moreover, unraveling the complexities of nanoparticle interactions within the intricate tumor microenvironment remains an ongoing endeavor, necessitating interdisciplinary collaboration and innovative research efforts.

Final Reflections:

In essence, targeted nanomedicine epitomizes the fusion of precision and innovation in the fight against cancer. As we navigate the uncharted territories of personalized therapy, fueled by the promise of nanotechnology, we stand at the threshold of a new era in cancer treatment. With concerted efforts and unwavering dedication, targeted nanomedicine holds the potential to revolutionize cancer therapy, offering renewed hope and prospects for improved patient outcomes in the relentless battle against cancer.

CONCLUSION:

The exploration of targeted nanomedicine approaches marks a pivotal advancement in the quest for precision cancer therapy. Through this review, we have traversed the landscape of nanoparticle-based interventions, encapsulating the synthesis methodologies, targeting strategies, and burgeoning applications in cancer treatment.

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Received on 03.03.2024 Revised on 27.03.2025

Accepted on 24.11.2025 Published on 13.01.2026

Available online from January 17, 2026

Research J. Pharmacy and Technology. 2026;19(1):472-480.

DOI: 10.52711/0974-360X.2026.00069

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