MicroRNA-143-5p Suppresses ER-Positive Breast Cancer Development by Targeting Oncogenic HMGA2.

BACKGROUND: About 70%-80% of breast cancers (BCs) express estrogen receptors (ER-positive). MicroRNAs (miRNAs) are a group of small endogenous noncoding RNAs that play a critical regulatory role in cancer development and progression, including in BC. MiRNA deficiency promotes the development of BCs. MiR-143-5p is one of the most commonly dysregulated miRNAs in BC but its role as a tumor suppressor remains unclear. MATERIALS AND METHODS: MiR-143-3p and -5p expression in breast tissue was analyzed using TCGA and StarBase databases. Expression in BC subclasses and survival analyses were conducted. Clinical samples were collected, cell cultures created, and gene expression assays performed following previous studies. Protein expression, luciferase reporter, wound healing, DAPI staining, cell cycle, colony formation, spheroid, CD44 FACS, and proliferation assays were conducted following various protocols. RESULTS: Here, we find that both miR-143-3p and miR-143-5p levels are considerably lower in BC tissue compared to normal breast tissue and low miR-143 expression predicts poor prognosis in ER+ BC patients. In-depth analyses identified 3 miR-143-5p binding sites in the 3' untranslated region (UTR) of the DNA binding protein High Mobility Group AT-Hook 2 (HMGA2). Luciferase reporter assays using wild-type and mutant HMGA2 3'UTR sequences and Western blot analyses demonstrated that HMGA2 is a direct and bona fide miR-143-5p target in BC cells. In addition, we show that restoration of miR-143-5p expression suppresses metastasis-related features of ER+ BC cells, including reduced tumor cell migration, increased E-cadherin expression, and decreased vimentin and N-cadherin expression. Furthermore, miR-143-5p reduces cell proliferation, cell cycle entry, and stemness, while promoting apoptosis moderately. Finally, patient sample pathway analyses demonstrated that these mechanisms are also active in BC. CONCLUSIONS: Altogether, our findings shed new light on miR-143-5p's anticancer biological functions in BC progression by directly targeting HMGA2. This suggests that restoration of miR-143-5p could be a promising new therapeutic approach for the treatment of ER+ BC.

CD44 Suppression Improved the Chemosensitivity of HT-29 Colorectal Cancer Cells to 5-Fluorouracil and Inhibited Cell Migration.

Purpose: CD44 plays a pivotal role through tumorigenesis by regulating cancer cell metastasis, stemness, and chemosensitivity and is considered a promising therapeutic target for human cancers, including colorectal cancer (CRC). Therefore, the present research aimed to examine the simultaneous therapeutic effect of CD44 silencing and 5-fluorouracil (5-FU) on in vitro tumorigenesis of CRC cells. Methods: CD44 expression was initially evaluated in TCGA datasets and CRC tissues. Furthermore, functional analysis was performed on HT-29 CRC cells overexpressing CD44. The cells were transfected with CD44 siRNA and then treated with 5-FU. Consequently, to explore the combination therapy effect on cell viability, migration, apoptosis, and chromatin fragmentation, we performed MTT assay, scratch assay, Annexin V/PI staining and DAPI staining assays, respectively. The spheroid and colony formation assays were further employed to investigate stemness features. The gene expression at protein and mRNA levels were explored using western blotting and qPCR. Results: Our findings illustrated that CD44 was significantly overexpressed in CRC tissues compared to normal samples. The suppression of CD44 considerably promoted the chemosensitivity of HT-29 cells to 5-FU by apoptosis induction. Also, the combination therapy led to overexpression of apoptotic genes, including P53, caspase-3, and caspase-9, as well as downregulation of AKT1 expression. Furthermore, CD44 suppression, separately or combined with 5-FU, hindered stemness properties in HT-29 cells via downregulation of Sox2 and Nanog expression. Besides, the combination therapy remarkably downregulated MMPs and suppressed CRC cell migration. Conclusion: Considering its involvement in chemosensitivity to 5-FU, CD44 could be suggested as a potential target for improving the efficiency of CRC chemotherapy.

Nanoarchitecture-based photothermal ablation of cancer: A systematic review.

Photothermal therapy (PTT) is an emerging non-invasive method used in cancer treatment. In PTT, near-infrared laser light is absorbed by a chromophore and converted into heat within the tumor tissue. PTT for cancer usually combines a variety of interactive plasmonic nanomaterials with laser irradiation. PTT enjoys PT agents with high conversion efficiency to convert light into heat to destroy malignant tissue. In this review, published studies concerned with the use of nanoparticles (NPs) in PTT were collected by a systematic and comprehensive search of PubMed, Cochrane, Embase, and Scopus databases. Gold, silver and iron NPs were the most frequent choice in PTT. The use of surface modified NPs allowed selective delivery and led to a precise controlled increase in the local temperature. The presence of NPs during PTT can increase the reactive generation of oxygen species, damage the DNA and mitochondria, leading to cancer cell death mainly via apoptosis. Many studies recently used core-shell metal NPs, and the effects of the polymer coating or ligands targeted to specific cellular receptors in order to increase PTT efficiency were often reported. The effective parameters (NP type, size, concentration, coated polymers or attached ligands, exposure conditions, cell line or type, and cell death mechanisms) were investigated individually. With the advances in chemical synthesis technology, NPs with different shapes, sizes, and coatings can be prepared with desirable properties, to achieve multimodal cancer treatment with precision and specificity.

The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer.

The mTOR complex 1 (mTORC1) coordinates several important environmental and intracellular cues to control a variety of biological processes, such as cell growth, survival, autophagy, and metabolism, in response to energy levels, growth signals, and nutrients. The endoplasmic reticulum (ER) is a crucial intracellular organelle that is essential for numerous cellular functions, including the synthesis, folding, and modification of newly synthesized proteins, stress responsiveness, and maintainence of cellular homeostasis. mTOR-mediated upregulation of protein synthesis induces the accumulation of misfolded or unfolded proteins in the ER lumen, which induces ER stress, leading to activation of the unfolded protein response (UPR) pathway. Reciprocally, ER stress regulates the PI3K/AKT/mTOR signaling pathway. Therefore, under pathologic conditions, the cross-talk between the mTOR and UPR signaling pathways during cellular stress can critically affect cancer cell fate and may be involved in the pathogenesis and therapeutic outcome of cancer. Here, we discuss accumulating evidence showing the mechanism of action, interconnections, and molecular links between mTOR signaling and ER stress in tumorigenesis and highlights potential therapeutic implications for numerous cancers.

Mutant P53 in the formation and progression of the tumor microenvironment: Friend or foe.

TP53 is the most frequently mutated gene in human cancer. It encodes the tumor suppressor protein p53, which suppresses tumorigenesis by acting as a critical transcription factor that can induce the expression of many genes controlling a plethora of fundamental cellular processes, including cell cycle progression, survival, apoptosis, and DNA repair. Missense mutations are the most frequent type of mutations in the TP53 gene. While these can have variable effects, they typically impair p53 function in a dominant-negative manner, thereby altering intra-cellular signaling pathways and promoting cancer development. Additionally, it is becoming increasingly apparent that p53 mutations also have non-cell autonomous effects that influence the tumor microenvironment (TME). The TME is a complex and heterogeneous milieu composed of both malignant and non-malignant cells, including cancer-associated fibroblasts (CAFs), adipocytes, pericytes, different immune cell types, such as tumor-associated macrophages (TAMs) and T and B lymphocytes, as well as lymphatic and blood vessels and extracellular matrix (ECM). Recently, a large body of evidence has demonstrated that various types of p53 mutations directly affect TME. They fine-tune the inflammatory TME and cell fate reprogramming, which affect cancer progression. Notably, re-educating the p53 signaling pathway in the TME may be an effective therapeutic strategy in combating cancer. Therefore, it is timely to here review the recent advances in our understanding of how TP53 mutations impact the fate of cancer cells by reshaping the TME.

MiR-146a Restoration Suppresses Triple-Negative Breast Cancer Cell Migration: A Bioinformatic and In Vitro Study.

Purpose: Breast cancer is one of the most commonly diagnosed types of cancer worldwide. This cancer is treated with various methods like mastectomy, chemotherapy, hormone therapy, and radiotherapy. Among them, targeted therapy, like microRNA (miRNA) replacement therapy, is considered a new approach to treating breast cancer. Methods: Data analysis from TCGA datasets were used to investigate the expression of hsa-miR-146a-5p in breast cancer. MTT assay was used to evaluate the viability of MDA-MB-231 cells after hsa-miR-146a-5p ectopic expression. A wound-healing assay was used to observe migration in the MDA-MB-231 cell line and the effect of the hsa-miR-146a-5p ectopic expression on migration. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used as a method to determine the effect of the hsa-miR-146a-5p ectopic expression on the expression of CXCR4, ß-catenin, MMP2, MMP9, and Vimentin genes known to be involved in invasion and migration of MDA-MB-231 cells. Results: Our results indicated that hsa-miR-146a-5p is not involved in apoptosis in the MDAMB-231 cells, while it is highly effective in migration inhibition. MMP9, MMP2, CXCR4, and Vimentin expressions were suppressed by hsa-miR-146a-5p induction; however, it induced the expression of ß-catenin. Conclusion: Some non-coding RNAs, such as hsa-miR-146a-5p, are effective in breast cancer targeted therapy. As cancer is a complicated disorder, therefore the combination of therapies might lead to novel therapeutic strategies.

Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs.

Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of ncRNAs (microRNA, circular RNA and long ncRNA) in BC metabolism, including glucose, lipid and glutamine metabolism. Investigation of this aspect may not only alter the approaches of BC diagnosis and prognosis, but may also open a new avenue in using ncRNA-based therapeutics for BC treatment by targeting different metabolic pathways.

SSX addiction in melanoma propagates tumor growth and metastasis.

Cancer/testis antigens are receiving attention as targets for cancer therapy due to their germ- and cancer cell-restricted expression. However, many of these antigens are inconsistently expressed among cancer types and individual tumors. Here, we show that members of the SSX cancer/testis antigen family comprise attractive targets in the majority of melanoma patients, as SSX is expressed in more than 90% of primary melanomas and metastases and plays a critical role in metastatic progression. Accordingly, SSX silencing in melanoma mouse xenograft models reduced tumor growth and completely abolished the formation of metastatic lesions in lungs and livers. Mechanistically, we demonstrate that silencing SSX in melanoma cells induces cell cycle S-phase stalling, leading to proliferative arrest and enhanced apoptosis, which elucidates the inhibitory effect of SSX loss on tumor growth and colonization capacity. Silencing SSX further compromised the capacity of melanoma cells to migrate and invade, influencing these cells' capability to spread and colonize. Taken together, these studies highlight SSX proteins as pivotal targets in melanoma with implications for blocking metastatic progression.

MicroRNAs in the cancer cell-to-cell communication: An insight into biological vehicles.

Cell-to-cell communication networks have indispensable roles in coordinating various biological processes in cancer cells or altering metabolism activity in both cancer and non-cancer cells. Exosomes, migrasomes, ectosomes, apoptotic bodies, and exomeres belonging to the heterogeneous world of extracellular vesicles (EVs), which have gained significant attention in recent years due to their principal role in cell-to-cell communication, including Extracellular Circulating miRNAs (ECmiRNAs) as a rich cargo content. ECmiRNAs can be taken up by target cells to mediate heterotypic cell-interactions and facilitate recipient repression in neighboring cells. The complex of ECmiRNAs with EVs, proteins, and lipoproteins structures such as TLR, AGO protein complex, HDL, and LDL can be more effective as mediators between cancer cells. The mechanism of multidrug resistance and angiogenesis in cancer cells may be altered during special signaling of EVs-ECmiRNAs during cell-to-cell communication. Also, those complexes may serve as novel biomarkers in cancer prognostication.

The Role of microRNAs in Multidrug Resistance of Glioblastoma.

Glioblastoma (GBM) is an aggressive brain tumor that develops from neuroglial stem cells and represents a highly heterogeneous group of neoplasms. These tumors are predominantly correlated with a dismal prognosis and poor quality of life. In spite of major advances in developing novel and effective therapeutic strategies for patients with glioblastoma, multidrug resistance (MDR) is considered to be the major reason for treatment failure. Several mechanisms contribute to MDR in GBM, including upregulation of MDR transporters, alterations in the metabolism of drugs, dysregulation of apoptosis, defects in DNA repair, cancer stem cells, and epithelial-mesenchymal transition. MicroRNAs (miRNAs) are a large class of endogenous RNAs that participate in various cell events, including the mechanisms causing MDR in glioblastoma. In this review, we discuss the role of miRNAs in the regulation of the underlying mechanisms in MDR glioblastoma which will open up new avenues of inquiry for the treatment of glioblastoma.

MicroRNA-143 act as a tumor suppressor microRNA in human lung cancer cells by inhibiting cell proliferation, invasion, and migration.

BACKGROUND/AIM: MicroRNAs play crucial roles in controlling cellular biological processes. miR-143 expression is usually downregulated in different cancers. In this study, we focused on exploring the role of miR143 in NSCLC development. METHODS: Bioinformatics analyses were used to detect the expression level of miR-143 in lung tumors. The cells were transfected by pCMV-miR-143 vectors. The efficacy of transfection was verified by Flow cytometry. The influence of miR-143 replacement on NSCLC cells migration, proliferation, and apoptosis was detected using wound-healing assay, MTT assay, and DAPI staining, respectively. RESULTS: MTT assay revealed that overexpression of miR143 inhibited cell growth and proliferation. Scratch assay results demonstrated that restoration of miR143 suppressed cell migration. The qRT-PCR assay was further used to detect the assumed relationship between miR143 and apoptotic and metastatic-related genes. CONCLUSION: The findings showed that miR-143 could reduce cell proliferation, invasion, and migration by reducing CXCR4, Vimentin, MMP-1, Snail-1, C-myc expression level, and increasing E-cadherin expression levels in lung cancer cells and might be a potential target in NSCLC's targeted therapy.

The potential of B7-H6 as a therapeutic target in cancer immunotherapy.

Immune checkpoints are vital molecules that regulate T-cell function by activation or inhibition. Among the immune checkpoint molecules, the B7-family proteins are significantly involved in the immune escape of tumor cells. By binding to inhibitory receptors, they can suppress T-cell-mediated immunity. B7-family proteins are found at various stages of tumor microenvironment formation and promote tumorigenesis and tumor progression. B7-H6 (encoded by gene NCR3LG1) is a prominent member of the family. It has unique immunogenic properties and is involved in natural killer (NK) cell immunosurveillance by binding to the NKp30 receptor. High B7-H6 expression in certain tumor types and shortage of or low expression in healthy cells - except in cases of inflammatory or microbial stimulation - have made the protein an attractive target of research activities in recent years. The avoidance of NK-mediated B7-H6 detection is a mechanism through which tumor cells escape immune surveillance. The stimulation of tumorigenesis occurs by suppressing caspase cascade initiation and anti-apoptosis activity stimulation via the STAT3 pathway. The B7-H6-NKp30 complex on the tumor membrane activates the NK cells and releases both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). B7-H6 is highly expressed in a wide range of tumor cells, including glioma, hematologic malignant tumors, and breast cancer cells. Clinical examination of cancer patients indicated that the expression of B7-H6 is related to distant metastasis status and permits postoperative prognosis. Because of its unique properties, B7-H6 has a high potential be utilized as a biological marker for cancer diagnosis and prognosis, as well as a target for novel treatment options.

Downregulation of HMGA2 by Small Interfering RNA Affects the Survival, Migration, and Apoptosis of Prostate Cancer Cell Line.

Purpose: To investigate the downregulation of high mobility group AT-hook 2 (HMGA2)expression by small interfering RNAs (siRNAs) in PC3 prostate cancer cell line. HMGA2belongs to the non-histone chromatin-binding protein family that serves as a crucial regulator ofgene transcription. The overexpression of this gene is positively correlated with various prostatecancer (PC)-related properties. Thus, HMGA2 is an emerging target in PC treatment. This studyaimed to examine the impact of siRNAs targeting HMGA2 on the viability, migration, andapoptosis processes of the PC3 PC cell line. Methods: siRNA transfection was conducted with a liposome-mediated approach. The mRNAand protein expression levels for HMGA2 are evaluated by real-time polymerase chain reaction(qRT-PCR) and western blot analysis. The cytotoxic properties of HMGA2-siRNA were measuredby MTT assay on PC3 cells. The migration of PC3 cells was measured by implementing awound-healing assay. Apoptosis measurement was also quantified by TUNEL assay. Results: Transfection with siRNA significantly decreased both mRNA and protein levels of theHMGA2 gene in a dose-dependent manner after 48 hours. Also, we demonstrated that theknockdown of HMGA2 led to a reduction in cell viability, migration ability, and enhancedapoptosis of PC3 cells in vitro. Conclusion: Our findings recommend that the specific siRNA of HMGA2 may efficiently beable to decrease PC progression. Therefore, it may be a promising adjuvant treatment in PC.

Restoration of miRNA-143 Expression Inhibits Growth and Migration of MKN-45 Gastric Cancer Cell Line.

Purpose: Gastric cancer (GC) is one of the main causes of death from diseases, especially in developing countries. MicroRNAs (miRNAs) are important modulators of the messenger RNAs expression. Among these miRNAs, MiR-143 is a tumor suppressor miRNA and its irregular expression has been revealed in a diversity of malignancies such as GC. Methods: In this study, we have attempted to restore the miR-143 expression in MKN-45 cells by introducing pCMV-miR-143 plasmid vectors. The consequences of exogenous expression of miR-143 on cell proliferation and migration were assessed by MTT and scratch tests, respectively. In addition, the DAPI staining assay was applied for apoptosisquantification. Following miR-143 transfection, the changes in K-Ras, C-Myc, MMP9, Bax, Caspase-3, and Caspase-9 mRNA levels were assessed. Results: The results indicated that the enhanced expression of miR-143 had negative effects on MKN-45 cells proliferation and invasion. Moreover, decreased expressions of K-Ras, MMP9, and C-Myc and up-regulation of Bax, Caspase-3, and Caspase-9 as downstream targets of miR-143 were recognized. Conclusion: These experimental results indicate that reversing the miR-143 expression, by novel techniques, including miRNA replacement could be considered as an efficient approach to reduce cell survival and metastasis.

microRNA-193a-5p Suppresses the Migratory Ability of Human KATO III Gastric Cancer Cells through Inhibition of Vimentin and MMP-9.

Purpose: microRNA-193a-5p is one of the well-known tumor suppressor miRNAs in the body but in many cases, its expression became reduced in patients suffering from gastric cancer (GC). The main purpose of this study was to restore the function of this miRNA in human GC cells and investigating the effects of enhanced expression of miR-193a-5p on proliferation, apoptosis, and migration of GC cells upon in vitro transfection. Methods: The KATO III GC cells were treated with 100 nM of miR-193a-5p or negative control sequences. Following that, the MTT assay, flow cytometry assay, and wound-healing assay were applied to estimate the impacts of enhanced expression of this miRNA on the viability, apoptosis, and migration rate of the cells, respectively. Moreover, the total RNA was isolated and alterations in the mRNA expression ratio of migratory genes were measured by qRT-PCR techniques. Results: The findings designated that enhanced expression of miR-193a-5p suppressed the migratory ability of the cells, but had no significant effects on cell survival or apoptosis of the transfected cells. In addition, this inhibitory function of miR-193a-5p on the migration rate of the KATO III cell line occurs with concurrent suppression of vimentin and MMP-9 gene expression. Conclusion: It can be concluded that miR-193a-5p negatively influences the migratory ability of the cancerous cells and restoring its effects can be regarded as a promising target of future therapeutic interventions, especially for GC metastasis.

Inflammatory reflex disruption in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China, in late 2019 and caused coronavirus disease 2019 (COVID-19), which is still a global pandemic. In most infected people, SARS-CoV-2 can only cause moderate symptoms, while in other patients, it leads to severe illness and eventually death. Although the main clinical manifestation of COVID-19 is often seen in the lungs, this disease affects almost all body organs. The excessive and prolonged release of inflammatory cytokines that may occur in COVID-19 patients, known as cytokine storms, stimulates undesired immune responses and can cause various tissues damage. In the current review article, we focus on the potential advantages of the intrinsic cholinergic anti-inflammatory pathway (CAP) as the efferent arm of inflammatory reflex in COVID-19 management. Considering this endogenous protective mechanism against chronic inflammation, we focused on the effects of SARS-CoV-2 in the destruction of this anti-inflammatory system. Several studies indicated the interaction of SARS-CoV-2 with the alpha7 subtype of the nicotinic acetylcholine receptor as the effector molecule of the inflammatory reflex. On the other hand, neurological manifestations have increasingly been identified as significant extrapulmonary manifestations of COVID-19. The rational connection between these findings and COVID-19 pathogenesis may be an important issue in both our understanding and dealing with this disease. COVID-19 is deeply rooted in our daily life and requires an urgent need for the establishment of effective therapeutic options, and all the possible treatments must be considered for the control of such inflammatory conditions.

Restoration of miR-143 reduces migration and proliferation of bladder cancer cells by regulating signaling pathways involved in EMT.

MicroRNAs (miRNAs), a class of regulatory endogenous short RNAs, are involved in various biological functions by targeting the mRNA of multiple protein-coding genes and influencing their related signaling pathways. In this investigation, we upregulated microRNA-143 (miR-143) expression levels in bladder cancer (BC) EJ138 cells by pCMV-miR-143 vectors. The efficacy of transfection was verified by Flow cytometry. The influence of miR-143 overexpression on BC cells migration, proliferation, and apoptosis was detected using wound-healing assay, MTT assay, and DAPI and Annexin V/PI staining, respectively. The results demonstrated that upregulation of miR-143 in BC EJ138 cells leads to inhibited proliferation and migration. Also, restoration of miR-143 was negatively associated with the expression levels of metastatic, apoptotic, invasion, and EMT-related genes, including C-Myc, CXCR4, MDM2, Vimentin, Snail-1, and MMP-9, along with increased E-Cadherin and TP53 expression. Therefore, miR-143 may be considered a potential therapeutic target for BC.

MicroRNA-143 inhibits proliferation and migration of prostate cancer cells.

Background: Prostate cancer (PC) is one of the most prevalent types of malignancies in males. Here, we replaced the miRNA-143 in PC cells by using a vector-based miRNA-143 transfection approach.Materials and methods: The miRNA-143 vector was transfected into the cells and qRT-PCR was applied to assess the expression of target genes in PC3 cells. Also, the MTT, scratch wound-healing, and DAPI staining assays were done to assess the proliferation, migration, and apoptosis of the cells, respectively.Results: The findings of the qRT-PCR determined the enhanced expression of miRNA-143 and other cancer-associated genes. The MTT and wound-healing assays revealed the proliferation and migration reduction in the transfected cells in comparison to control cells that contain an empty vector.Conclusion: The miRNA-143 has a significant impact on cell growth and migration during PC metastasis, and it may be a promising candidate for molecular therapies of PC.

Glimpse into the Cellular Internalization and Intracellular Trafficking of Lipid- Based Nanoparticles in Cancer Cells.

Lipid-based nanoparticles, as drug delivery carriers, are commonly used for the delivery of anti-cancer therapeutic agents. Due to their smaller particle size and similarity to cell membranes, Lipid-based nanoparticles are readily internalized into cancer cells. Cancer cells also overexpress receptors for specific ligands, including folic acid, hyaluronic acid, and transferrin, on their surface, thus, allowing the use of their ligands for surface modification of the lipid-based nanoparticles for their specific recognition by receptors on cancer cells. This would also allow the gradual intracellular accumulation of the targeted functionalized nanoplatforms. These ligand-receptor interactions eventually enhance the internalization of desired drugs by increasing the nanoplatforms cellular uptake. The cellular internalization of the nanoplatforms varies and depends on their physicochemical properties, including particle size, zeta potential, and shape. The cellular uptake is also influenced by the types of ligand internalization pathways utilized by cells, such as phagocytosis, macropinocytosis, and multiple endocytosis pathways. This review classifies and discusses lipidbased nanoparticles engineered to carry specific ligands, their recognition by receptors on cancer cells, and their cellular internalization pathways. Moreover, the intracellular fate of nanoparticles decorated with specific ligands and their best internalization pathway (caveolae-mediated endocytosis) for safe cargo delivery are also discussed.