Nanoformulation Strategies to Overcome Multi-Drug Resistance in Cancer: From Pharmacological Characterization to Preclinical Translation

Multi-drug resistance (MDR) remains the most formidable pharmacological barrier to effective cancer chemotherapy, accounting for treatment failure in the majority of patients with advanced or recurrent disease. MDR arises through diverse mechanisms that collectively reduce intracellular drug concentrations below therapeutic thresholds. Conventional chemotherapeutic regimens frequently fail to account for the dynamic, spatially heterogeneous nature of MDR within the tumor microenvironment. Advanced nanoformulations offer a mechanistically grounded strategy to circumvent these resistance pathways: by encapsulating cytotoxic payloads within engineered nanocarriers, they can evade efflux pump recognition, enable spatiotemporally controlled co-delivery of chemosensitizers alongside primary agents, and exploit receptor-mediated endocytosis to bypass transporter-dependent efflux. A rigorous pharmacological and translational framework is urgently needed to systematically evaluate these approaches from formulation design through to preclinical proof-of-concept.This Research Topic aims to consolidate cutting-edge research at the intersection of nanomedicine, cancer pharmacology, and translational science, specifically targeting the challenge of MDR. While promising nanoformulation strategies have been reported in isolated studies, the field lacks a coherent body of evidence that maps the relationship between nanocarrier physicochemical properties and MDR circumvention mechanisms, utilizes computational models or artificial intelligence (AI) to accelerate formulation optimization, and designs advanced nanomedicines specifically targeting cancer stem cells (CSCs). Furthermore, there remains a critical need to characterize the pharmacokinetics, biodistribution, and theranostic potential of candidate systems in resistant tumor models, benchmarking formulations against regulatory-relevant preclinical endpoints required for investigational new drug (IND) filing.This Research Topic seeks to address these gaps by bringing together research that: (1) elucidates the mechanistic basis by which nanoformulations overcome specific resistance pathways; (2) leverages computational and intelligent design approaches to optimize formulation development; (3) defines pharmacokinetic and biodistribution determinants in MDR and cancer stem cell models; and (4) advances GMP-compatible formulation strategies, nanotheranostics, and preclinical safety profiling that support clinical translation and regulatory science. By integrating pharmacological depth with translational rigor, this RT aims to accelerate the development of clinically viable nanomedicines for drug-resistant cancers.We welcome original research articles, reviews, mini-reviews, perspectives, and methods papers focused on nanoformulation-based strategies to overcome MDR in cancer, with an explicit pharmacological and/or translational dimension. Priority themes include:• AI-guided nanoformulation design, modeling, and optimization• Tumor microenvironment-responsive and stimuli-triggered nanocarriers targeting MDR niches• Cancer stem cell-targeted nanomedicines to circumvent therapy resistance and recurrence• Nanotheranostics integrating real-time diagnostic imaging with MDR-reversal therapeutics• Nanocarrier-mediated efflux pump inhibition or evasion (e.g., P-gp, BCRP, MRP)• Co-delivery systems for chemosensitizer–drug combinations• ADMET characterization and pharmacokinetic/pharmacodynamic (PK/PD) modeling in drug-resistant cancer models• Clinical translation, regulatory science, and GMP-compatible formulation development• Preclinical safety and efficacy data packages aligned with regulatory requirements (IND-enabling studies)Studies must demonstrate selectivity toward cancer cells across multiple cell lines and provide detailed characterization of formulation composition and stability. Manuscripts focused solely on natural product extracts, cancer prognosis, or therapy-related side effects are outside the scope of this section. Topic editors: Dr. Jitu Halder, JANEESH PLAKKAL AYYAPPAN, Zideng Dai Source: https://www.frontiersin.org/research-topics/84541/nanoformulation-strategies-to-overcome-multi-drug-resistance-in-cancer-from-pharmacological-characterization-to-preclinical-translation