Chitosan-Lactobacillus Nanoparticles Combat Colon Cancer

In a groundbreaking study published in the esteemed journal BMC Cancer, researchers have unveiled promising anti-cancer properties of a novel nanoparticle formulation combining chitosan and the secretome of Lactobacillus acidophilus. This innovative therapeutic approach targets crucial signaling pathways implicated in colorectal cancer (CRC), a malignancy ranking as the second leading cause of cancer-related mortality globally. By focusing on the colon adenocarcinoma Caco-2 cell line, the research team has charted a new frontier in CRC treatment modalities that holds the potential to revolutionize patient outcomes.

Colorectal cancer continues to pose significant challenges to health systems worldwide due to its high incidence and mortality rates. The search for effective, targeted treatment strategies remains an urgent imperative. In this context, the integration of nanotechnology with microbiome elements has opened a promising avenue of investigation. The use of chitosan nanoparticles (CSNP), a biocompatible and biodegradable polysaccharide derived from chitin, serves as a robust and versatile delivery system. When conjugated with the secretome—the collection of bioactive factors secreted—of the probiotic Lactobacillus acidophilus (L.a-sup), the resultant nanoparticle complex (CSNP/L.a-sup) exhibits striking potential in modulating cancer-related cellular pathways.

The researchers employed an ionic gelation method to synthesize the CSNP/L.a-sup complex. This technique allows for precise control over particle size and distribution, yielding particles averaging 478.6 nanometers in diameter with a negative zeta potential of -8.9 millivolts. Such physicochemical properties are crucial as they influence the biodistribution, cellular uptake, and bioactivity of nanoparticles within biological environments. Scanning electron microscopy further confirmed the morphology and surface characteristics of the nanoparticles, emphasizing their suitability for biomedical applications.

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Encapsulation efficiency (EE) metrics revealed that approximately 74.6% of the bioactive proteins from the Lactobacillus acidophilus secretome were successfully incorporated into the chitosan matrices. Moreover, the release profile demonstrated that nearly 76% of these proteins were discharged under mildly acidic conditions (pH ~6.8) within 48 hours. This pH-sensitive release is particularly relevant given the tumor microenvironment’s characteristic acidity, enhancing targeted delivery and therapeutic efficacy while minimizing systemic side effects.

Safety assessment through cytotoxicity analysis indicated a high viability of Caco-2 colon cancer cells and human dermal fibroblast (HDF) cells upon exposure to CSNP/L.a-sup, with survival rates of 85.5% and 92.6%, respectively. These findings underscore the biocompatibility of the nanoparticles, essential for any prospective clinical application. The time-dependent uptake of CSNP/L.a-sup by Caco-2 cells, with significant internalization noted as early as one hour and peaking at three hours, further affirms the efficient cellular internalization dynamics that are vital for therapeutic action.

At the molecular level, the CSNP/L.a-sup exerted significant regulatory effects on key genes implicated in CRC pathogenesis. Notably, there was a marked downregulation of β-Catenin, TGF-α, and TGF-β expression levels, with reductions to 42%, 79%, and 16% of baseline expression, respectively. The suppression of β-Catenin is particularly noteworthy, given its pivotal role in the Wnt signaling pathway, which is frequently dysregulated in colorectal cancer, driving uncontrolled cell proliferation and tumor progression.

Conversely, the nanoparticle complex induced a dramatic upregulation of tumor suppressor genes PTEN and caspase-9, with expression surges of approximately 42-fold and 114-fold, respectively. PTEN functions as a major antagonist of oncogenic signaling cascades, including the PI3K/AKT pathway, and its restoration is associated with reduced tumor growth and metastasis. The amplification of caspase-9 expression signifies enhanced apoptotic activity, facilitating programmed cell death within malignant cells and thus curbing tumor viability.

Interestingly, the differential gene expression patterns imply compartment-specific actions of the nanoparticle components. The suppression of TGF-α seems more intimately linked with the chitosan nanoparticle vehicle itself, while the upregulation of PTEN appears predominantly attributable to the Lactobacillus acidophilus secretome. This suggests a synergistic mode of action where the nanocarrier and its bioactive payload harmonize to maximize anti-cancer effects.

The potential of probiotic-derived secretome factors to influence tumor biology is a frontier area of oncological research. The secretome encompasses a milieu of proteins, peptides, metabolites, and extracellular vesicles that can modulate immune responses, inflammation, and cell signaling pathways. By harnessing this biological reservoir within a nanostructured delivery platform, the study achieves a convergence of advances in microbiology, nanomedicine, and cancer therapeutics.

Beyond in vitro assessments, the implications of this study stretch toward translational and clinical realms. The use of biocompatible materials like chitosan ensures minimal toxicity, while the probiotic secretome offers a rich source of multifunctional biomolecules with intrinsic anti-neoplastic properties. This integrative approach mitigates common limitations in chemotherapy, such as off-target toxicity and drug resistance, opening avenues for safer, more targeted interventions.

Moreover, the observed gene expression modulations correspond closely with pathways implicated in treatment resistance and disease recurrence. By simultaneously dampening oncogenic drivers and bolstering tumor suppressor mechanisms, CSNP/L.a-sup nanoparticles embody a multi-pronged therapeutic strategy, potentially overcoming hurdles that have long impeded colorectal cancer management.

The study’s meticulous characterization of nanoparticle parameters and biological effects establishes a foundation for future optimization, including in vivo validation, pharmacokinetics, and scaling for clinical-grade production. The dynamics of protein release at tumor-relevant pH levels highlight the controlled delivery capabilities essential for maximizing efficacy while minimizing systemic exposure.

Furthermore, the integration of probiotic secretome components aligns with emerging paradigms recognizing the gut microbiome’s influential role in cancer pathogenesis and therapy response. This research exemplifies how leveraging microbiota-derived factors can complement conventional anticancer agents, contributing to a holistic understanding of tumor microenvironment interactions.

Amidst global efforts to expand the oncological arsenal, this study’s contribution is timely and impactful. It not only charts a feasible method to enhance drug delivery using natural polymers but also reveals novel mechanistic insights into probiotic secretome-driven modulation of cancer cell signaling. Such dual-faceted innovation is poised to inspire a wave of biomaterial and microbiome-inspired therapeutic development.

While challenges remain before clinical translation, including comprehensive toxicity profiling and efficacy testing in animal models, the promise of chitosan/Lactobacillus acidophilus secretome nanoparticles heralds a new chapter in precision oncology. The interdisciplinary fusion embodied in this work reflects the future trajectory of cancer research, where nanotechnology, molecular biology, and microbiology converge to combat a complex and devastating disease.

In summary, the research outlined in BMC Cancer reveals that the CSNP/L.a-sup nanoparticle not only modulates pivotal signaling pathways of colorectal cancer but does so with favorable safety profiles and targeted delivery capabilities. This synergistic formulation represents a compelling addition to anticancer strategies, potentially transforming therapeutic outcomes for patients battling CRC worldwide. The promising data serve as a clarion call for further exploration into nano-probiotic therapeutics, advocating a paradigm shift toward bioinspired, multifunctional cancer treatments.

Subject of Research: Anti-cancer effects of chitosan nanoparticles combined with Lactobacillus acidophilus secretome on colorectal cancer signaling pathways in Caco-2 cell line.

Article Title: Anti-cancer properties of chitosan / Lactobacillus acidophilus secretome nanoparticle on signaling pathways of colorectal cancer in colon adenocarcinoma (Caco-2) cell line.

Article References:
Saberpour, M., Maqsoodi, R. & Bakhshi, B. Anti-cancer properties of chitosan / Lactobacillus acidophilus secretome nanoparticle on signaling pathways of colorectal cancer in colon adenocarcinoma (Caco-2) cell line. BMC Cancer 25, 983 (2025). https://doi.org/10.1186/s12885-025-14315-5

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14315-5

Tags: advancements in cancer research methodologiesbiocompatible cancer therapiesbiodegradable polysaccharides in medicinecancer signaling pathways modulationChitosan nanoparticles in cancer therapycolorectal adenocarcinoma researchcolorectal cancer treatment innovationsLactobacillus acidophilus secretomenanoparticle delivery systemsnanotechnology in cancer treatmentprobiotics in cancer therapytargeted cancer treatment strategies