Nanomedicine Strategies to Overcome Multi-Drug Resistance in Cancer: Innovations in Targeted Delivery, Tumor Microenvironment Modulation and Synergistic Therapies

Multi-drug resistance (MDR) remains a major health challenge in the cancer treatment, leading to treatment failure and disease recurrence. Recent advancements in nanomedicine have introduced innovative approaches to treat MDR by improving drug delivery, reducing systemic toxicity, and re-sensitizing resistant cancer cells. This review provides a comprehensive summary of various nanocarrier systems that have been developed to bypass drug efflux mechanisms, promote intracellular drug accumulation, and permit controlled release. These nanocarrier systems include liposomes, polymeric nanoparticles, metal-based nanoparticles, and supramolecular constructs. Additionally, we discuss approaches targeting the tumor microenvironment, such as reprogramming tumor-associated macrophages (TAMs), reversing immunosuppression, and manipulating cancer stem cell differentiation. Special attention is paid to co-delivery systems that combine chemotherapeutics with gene therapies, redox-active compounds, autophagy inhibitors, and nitric oxide donors to produce synergistic anticancer effects. Novel strategies such as ferroptosis-inducing nanodrugs, stimuli-responsive platforms, and ultrasonic or photothermic based improved therapies are emphasized for their ability to evade typical resistance pathways. We also go over the important examples where nanotechnology has been utilized to counter MDR specifically in colorectal, ovarian, glioblastoma, and non-small cell lung cancer, targeting mechanisms such as P-glycoprotein overexpression, MRP2 transport, MGMT-mediated repair, and EGFR-TKI resistance. While promising preclinical results highlight the translational potential of nanomedicine for overcoming MDR, clinical integration remains a challenge. Key obstacles include scalable manufacturing, regulatory alignment, and thorough safety validation. This review aims to inform the rational design and clinical translation of nanotechnology-enabled therapeutics for drug-resistant cancers by integrating mechanistic insights with nanoplatform innovation.