Phospholipid-Drug Conjugates in Cancer Therapy: Emerging Paradigms and Future Directions.

Phospholipid-drug conjugates (PDCs) represent a novel advancement in cancer therapy, combining the therapeutic potential of active drug molecules with the biocompatibility and targeting benefits of phospholipids. Conventional cancer treatments face limitations such as drug resistance, off-target toxicity, and poor solubility. PDCs address these issues by enhancing drug stability, bioavailability, and targeted delivery, reducing systemic toxicity. Their amphiphilic nature enables self-assembly into nanocarriers, allowing controlled and site-specific drug release. PDCs utilize both passive and active targeting mechanisms, with the enhanced permeability and retention (EPR) effect facilitating tumor accumulation and ligand-receptor interactions enhancing active targeting. Stimuli-responsive PDCs further improve specificity by releasing drugs in response to tumor microenvironment factors such as acidity and enzymatic activity. Recent advances in PDC synthesis, including covalent bonding strategies, modular designs, and bio-inspired approaches, have broadened their therapeutic potential. Their integration with nanotechnology and gene-based therapies presents new possibilities for precision medicine and personalized treatment. Despite these benefits, challenges such as scalability, regulatory hurdles, and multidrug resistance (MDR) remain. Research is addressing these issues through AI-driven optimization, bioprinting-based formulations, and sustainable green chemistry. Future applications extend beyond oncology, with potential uses in neurodegenerative, infectious, and cardiovascular diseases. Overall, PDCs hold tremendous promise in transforming cancer treatment, offering safer, more effective, and highly targeted therapies that could revolutionize patient outcomes and therapeutic precision.