Amogh Reddy Badikol, Karthik Mangu, Abha Ravikumar Mundada, Md. Rizwanullah
• Polysaccharide nanocarriers exhibit excellent biocompatibility, biodegradability, and functional versatility. • Natural polysaccharide-based nanoparticles enhance the solubility, bioavailability, and tumor-targeting potential of PTX. • Passive, active, and stimulus-responsive targeting strategies enhance therapeutic efficacy and minimize systemic toxicity. • Emerging formulations demonstrate enhanced tumor accumulation, controlled drug release, and reduced off-target effects in preclinical models. • Co-delivery of PTX with genes, phototherapeutics, or MDR modulators enhances anticancer outcomes. Paclitaxel (PTX) is a potent chemotherapeutic agent widely employed in the treatment of various solid tumors; however, its clinical success is hampered by poor aqueous solubility, pre-systemic metabolism, non-specific biodistribution, and systemic toxicity. In recent years, nanotechnology-driven delivery systems, especially those derived from natural polysaccharides, have shown great promise in overcoming these limitations. This review provides an in-depth analysis of the physicochemical properties, pharmacokinetics, and mechanisms of action of PTX, alongside its delivery challenges in conventional formulations. Emphasis is placed on the design and application of natural polysaccharide-based nanoparticles (NPs), including those derived from chitosan, hyaluronic acid, cyclodextrin, alginate, dextran, pullulan, inulin, pectin, and cellulose derivatives. These biopolymers exhibit unique advantages such as biocompatibility, biodegradability, ease of functionalization, and responsiveness to tumor-specific stimuli (e.g., pH, redox, enzymes). Targeting strategies like passive targeting, active ligand-mediated, and stimuli-responsive mechanisms are critically examined. Furthermore, we highlight recent advances in PTX-loaded polysaccharide NPs engineered for co-delivery of anticancer agents, gene silencing molecules, and phototherapeutics, aiming to enhance therapeutic efficacy and overcome PTX resistance in cancer. Finally, the translational challenges and prospective directions for clinical advancement are discussed. Overall, this review highlights the remarkable potential of natural polysaccharide-based NPs to improve the therapeutic index of PTX and sets the stage for their translation into next-generation personalized cancer therapies.