PC is often referred to as the “king of cancers” due to its difficult treatment, low survival rates, and poor prognosis. Despite advancements in diagnostic technologies in recent years, the incidence of PC continues to rise. Although the five-year survival rate has improved, PC remains one of the malignancies with the poorest prognosis [1]. The one-year survival rate after diagnosis is only 24 %, while the five-year survival rate is approximately 9 %. Three major issues in PC administration are the main causes of this poor prognosis. First of all, the early symptoms are vague and easy to miss, which causes recognition to be delayed. Second, even in high-risk population screening programs, early-stage tumor detection by conventional imaging is quite challenging due to the pancreas' deep abdominal location. Third, PC has extremely aggressive biological features, including fast tumor cell growth and dissemination, which quickly progresses from precancerous lesions to advanced, symptomatic illness [2,3]. As a result, between 80 % and 85 % of PC patients are identified with metastatic or incurable illness at first presentation, missing the chance for curative surgical resection [4,5]. A considerable percentage of patients do not meet surgical requirements, even if they have resectable tumors [6].

PC is clinically classified into four stages based on tumor progression: early, intermediate, late-intermediate, and advanced. In the early stage, tumors are confined to the pancreas and typically present with no symptoms or only mild dyspepsia—further contributing to delayed diagnosis. As the disease progresses to the intermediate stage, tumors enlarge and invade surrounding tissues, causing symptoms such as jaundice, abdominal pain, and weight loss. In the late-intermediate stage, tumor invasion extends to major blood vessels and lymph nodes, exacerbating digestive dysfunction and pain. By the advanced stage, widespread metastasis occurs, leading to severe cachexia, multi-organ failure, and systemic symptoms like fever and fatigue [7].

Against this backdrop of diagnostic and prognostic challenges, standard treatment modalities for PC have been developed to address different disease stages [8]. Early-stage PC is primarily treated with surgical resection, including pancreaticoduodenectomy, pancreatic body-tail resection, and total pancreatectomy [9]. For intermediate and late-intermediate PC, chemotherapy and radiotherapy are commonly used to reduce tumor size and improve the possibility of subsequent surgical resection. In advanced-stage PC, distant metastases necessitate systemic therapy, with chemotherapy as the primary modality to control disease progression [10].

However, conventional treatments—particularly chemotherapy, the primary treatment for advanced PC—encounter substantial limitations that prove ineffective in addressing the inherent challenges posed by PC. First, chemotherapeutic drugs exhibit non-selective toxicity, resulting in the damage of both tumor and normal cells. Adverse effects such as bone marrow suppression, gastrointestinal reactions, and neurotoxicity are also caused by these drugs. These side effects limit drug dosage and duration, thereby compromising therapeutic efficacy. Secondly, PC cells frequently exhibit intrinsic or acquired chemoresistance, resulting in treatment failure. Thirdly, conventional chemotherapy regimens offer minimal survival benefits and demonstrate only a slight improvement in overall patient survival rates [11]. Even standard regimens such as gemcitabine are hindered by low bioavailability and short half-life, further reducing their effectiveness [12].

Given the severe side effects, high drug resistance, and limited survival benefits of conventional therapies, there is an urgent need to explore more precise, efficient, and less toxic treatment modalities. Targeted drug delivery systems—capable of specifically accumulating at tumor sites while reducing off-target toxicity—offer new hope for addressing PC’s diagnostic and therapeutic challenges and improving patient outcomes [13,14]. These systems are categorized into passive and active targeting: passive targeting relies on the high permeability of tumor vasculature and lack of lymphatic drainage, allowing nanocarriers to accumulate at tumor sites via passive accumulation. A typical passive targeting formulation, nano-liposome irinotecan (nal-IRI) [15], has been clinically used for PC treatment: The US FDA approved a first-line treatment regimen for metastatic pancreatic adenocarcinoma in May 2024: the NALIRIFOX regimen, which combines nano-liposome irinotecan (nal-IRI) with oxaliplatin, fluorouracil, and calcium folinic acid [16]. Compared to traditional irinotecan, nal-IRI shows superior efficacy (prolonged median overall survival in the NAPOLI-1 trial) [17], lower toxicity, and optimized pharmacokinetics; its combination regimen also outperforms Tegio monotherapy in second-line treatment [18]. Beyond liposomes, passive targeting carriers such as carbon nanotubes (CNTs), exosomes (EXOs), polymeric micelles (PMs), and nanocrystals (NCs) further leverage PC’s unique microenvironment (e.g., EPR effect) to enhance drug precision and reduce toxicity [19,20]. Active targeting, by contrast, achieves precise delivery via ligand-receptor binding to overexpressed molecules on PC cells.

To provide researchers with a comprehensive understanding of the design of active targeting systems for PC and to promote the development and clinical translation of novel targeted drug delivery systems for PC, this review focuses on the design strategies of active targeted drug delivery systems for PC—on the basis of introducing passive targeting carriers and their clinical applications. The review covers therapeutic agents for PC, drug carriers for PC, overexpressed antigens and receptors in PC, as well as antibodies and ligands used to mediate active targeting of PC cells.