Cancer is a serious threat to global health, with nearly 3 million PubMed entries focused on the subject [1], [2]. Early detection and therapy are the main goals of cancer research, as cancer originates from cellular mutations that lead to aberrant tumour development. During metastasis, cancer cells spread through the lymphatic and blood vessels, forming tumours in other areas of the body [4]. While metastasis complicates treatment and increases mortality, early detection often makes cancer curable [3]. Conventional tumour treatments, including radiation therapy, chemotherapy, and surgery, have significant drawbacks and present a major health risk globally. Chemotherapy lacks specificity, affecting both cancerous and healthy cells; radiation harms surrounding tissues; and surgery cannot effectively address metastases. The primary goal of cancer therapy is to minimize damage to normal cells while maximizing specificity in targeting malignant cells. Despite being necessary, radiation and chemotherapy often cause serious side effects and do not always lead to full remission. While higher doses and combination therapies can improve outcomes, they also increase toxicity [1], [3].

Targeted drug delivery systems offer a promising approach by reducing systemic toxicity, improving therapeutic efficacy, and ultimately enhancing patient survival rates [5]. Fig. 1 explains the workflow of receptor-mediated drugs in cancer. These systems work by delivering drugs specifically to tumour areas using nanotechnology, sparing healthy cells [5]. Nanoparticle-based drug delivery relies on the enhanced permeability and retention (EPR) effect to improve pharmacokinetics, bioavailability, and overall efficacy. Both passive and active targeting contribute to reduced dosages, fewer side effects, and better therapeutic outcomes [3]. When used alone or in combination, modern anticancer drugs such as 5-fluorouracil, paclitaxel, cisplatin, and docetaxel commonly used for oral cancer treatment can cause significant harm to healthy cells due to their non-specific distribution and severe side effects. Furthermore, these drugs' limited absorption and low solubility hinder their effectiveness. Researchers are working to improve oral, buccal, and intravenous therapies by developing nano-based drug carriers, aiming to enhance the safety and efficacy of treatments [6]. Malignant bone tumours, challenging to treat with current methods, can benefit from nanoparticle-based approaches. NPs enhance diagnosis through improved imaging and receptor-targeted drug delivery, increasing drug accumulation at tumour sites while minimizing toxicity, offering promise for personalized bone cancer treatment [7].

Receptor-specific ligands, such as those targeting epidermal growth factor (EGF) receptors, play a key role in enhancing active cellular internalization, improving therapeutic efficacy, and promoting tumour-specific accumulation by leveraging the leaky vasculature of tumours [8]. Ligand/receptor-mediated systems specifically target receptors overexpressed at disease sites with selected ligands, potentially in combination with pH-dependent systems for gastrointestinal stability. This improves treatment efficacy for colonic diseases while reducing side effects [9]. Despite advancements in cancer treatment, the field remains a critical research focus due to high mortality rates and the risk of recurrence. Emerging developments aim to target specific cancer cell surface receptors to deliver therapies more efficiently, non-invasively, and cost-effectively [10].

Drug resistance and off-target effects remain significant obstacles in cancer treatment. One promising solution is receptor-mediated endocytosis (RME), which targets overexpressed receptors on cancer cells and improves therapeutic specificity and efficacy. This approach utilizes ligands such as cell-penetrating peptides (CPPs), tumour-homing peptides (THPs), and monoclonal antibodies (mAbs) [11]. RME has gained recognition for its high selectivity and enhanced delivery efficiency, driven by ligand-receptor binding. While it introduces added complexity, cost, and the possibility of off-target effects, it enables the design of customized treatments for different therapies [1].

In recent years, an expanding body of research has explored RMDD’s application in diverse cancer types, including solid tumour and metastatic cancers. While some reviews have addressed various aspects of targeted drug delivery, few comprehensive analyses focus specifically on receptor-mediated strategies, particularly in light of recent technological advances. Given the rapid progression of research in this area, a timely review that examines RMDD's translational potential in cancer therapy is essential. This review article fills a gap by offering an in-depth analysis of receptor-targeted systems in cancer treatment. We explore topics such as the role of receptors in cancer progression and metastasis, the types of ligands used in targeting, advances in receptor-targeted nanoparticle engineering, and innovative strategies like receptor-targeted imaging for early diagnosis and treatment monitoring. By integrating these developments, this review provides a cohesive understanding of RMDD's role in advancing cancer treatment.