Design of Multi-Stimuli Responsive Nanocarriers for Co-delivery of Phytochemicals and Immune Modulators: A Synergistic Approach to Overcoming Tumor Resistance

Abstract

Overcoming therapeutic resistance continues to be a major obstacle in cancer treatment, driven by intrinsic survival pathways within tumor cells and the immunosuppressive pressures exerted by the tumor microenvironment (TME). Recent advances in nanotechnology have enabled the design of multi stimuli responsive delivery system
capable of releasing a therapeutic agent in a controlled and site-specific manner by exploiting characteristic tumor cues such as acidic pH, elevated reactive oxygen species, high intracellular glutathione, and dysregulated
enzymatic activity. This review examines the rationale for co-delivering phytochemicals and immune-modulating agents, two classes of therapeutics that act through complementary mechanism although not always synchronized. Although phytochemicals such as curcumin, quercetin, and resveratrol possess antioxidant, anti-inflammatory, and
pro-apoptotic properties, their clinical translation is limited by poor solubility, rapid metabolism, and inconsistent bioavailability, conversely immune modulators, including checkpoint inhibitors and cytokine-based therapeutics, can restore antitumor immunity but often show limited benefit in tumor with weak immunogenicity or exhausted
immune cell phenotypes. Incorporating these agents into intelligent nanocarriers constructed from biodegradable polymer, for example, poly(lactic-co-glycolic acid)-poly(ethylene glycol) chitosan, inorganic matrices, for example, mesoporous silica gold nanoparticles or hybrid lipid polymer platforms provide a means of achieving synergistic therapeutic activity, although formulation complexity remains a challenge. Advanced encapsulation strategies, including co-loading within single nanoparticles
layer-by-layer architectures and core-shell nanogels allows for precise coordination of drug release, enabling immune activation followed by cytotoxic or regulatory effects, but sometimes overlapping release profiles occur. Preclinical investigations of combinations such as curcumin with anti-programmed death ligand 1, resveratrol with interleukin 2 (IL-2), and quercetin with small interfering RNAs, as well as emerging approaches involvingepigallocatechin gallate/IL-12 or berberine/anti- cytotoxic T lymphocyte associated antigen-4 demonstrates enhanced immune cell recruitment, suppression of resistance pathway, and remodeling of the TME toward a more immunoreactive state. However, results vary between models. Collectively, these finding highlights the potential of multi-stimuli responsive nanoplatforms as a strategy to integrate phytochemical activity with immune modulation for improved antitumor efficacy, although clinical translation remains to be fully realized